Table 1 Frequency of cryptic splice-altering MYBPC3 variants in a large cohort of HCM probands.

From: Identification of an elusive spliceogenic MYBPC3 variant in an otherwise genotype-negative hypertrophic cardiomyopathy pedigree

vID	GRCh38 NC_000011.10	GRCh37 NC_000011.9	Coding DNA NM_000256.3	L	HCM (n)	HCM (%)	SpliceAI Δ score	Splicing defect	Deduced effect on the TRF	Ref	dbSNP ID	ClinVar	ClinVar ID	gnomAD
v1	g.47351515C>T	g.47373066C>T	c.26−10G>A	i1	2	0.021	0.39	E2sk	In-frame (del 89 aa)	²¹	rs397515978	US	42,643	NA
v2	g.47350117G>A	g.47371668G>A	c.407−5C>T	i3	2	0.021	0.18	E4sk	In-frame (del 33 aa)	²¹	rs371312567	LB	414,443	4.24E−05
v3	g.47350009C>G	g.47371560C>G	c.505+5G>C	i4	1	0.010	0.86	E4tr	Frameshift—PTC	⁴⁷	rs727503219	LP	164,151	NA
v4	g.47350008A>C	g.47371559A>C	c.505+6T>G	i4	0	0	0.85	E4sk	In-frame (del 33 aa)	²¹	rs397516055	US	42,762	NA
v5	g.47349769C>G	g.47371320C>G	c.654+5G>C	i5	1	0.010	0.62	E5tr	In-frame (del 16 aa)	¹⁷	rs397516066	US	263,572	NA
v6	g.47349769C>T	g.47371320C>T	c.654+5G>A	i5	1	0.010	0.50	E5sk	Frameshift—PTC	²¹	rs397516066	US	42,782	NA
v7	g.47348566T>C	g.47370117T>C	c.655−25A>G	i5	1	0.010	0.19	E6sk	Frameshift—PTC	⁴⁸	NA	NA	NA	NA
v8	g.47347854C>A	g.47369405C>A	c.821+3G>T	i7	1	0.010	0.71	E7sk	Frameshift—PTC	¹⁷	rs727503213	US/LP/P	228,869	NA
v9	g.47347852C>T	g.47369403C>T	c.821+5G>A	i7	2	0.021	0.86	E7sk	Frameshift—PTC	^3,21	rs397516077	US/LP/P	42,796	NA
v10	g.47347065C>T	g.47368616C>T	c.906−36G>A	i9	9	0.094	0.91	pRi9/E10ext	Frameshift—PTC	^16,49	rs864622197	LP/P	219,660	NA
v11	g.47347037A>G	g.47368588A>G	c.906−8T>C	i9	0	0	0.12	E10sk	In-frame (ins 1 aa, del 2 aa)	²¹	rs370245341	LB	922,256	8.78E−06
v12	g.47346623T>C	g.47368174T>C	c.926+4A>G	i11	0	0	0.40	E11sk	In-frame (ins 1 aa, del 7 aa)	²¹	rs397516081	US	42,803	NA
v13	g.47346380G>T	g.47367931G>T	c.927−10C>A	i11	0	0	0.45	E12sk	Frameshift—PTC	²¹	rs201078659	LP	42,805	NA
v14	g.47346379C>T	g.47367930C>T	c.927−9G>A	i11	12	0.125	0.28	E12sk	Frameshift—PTC	^21,50,51	rs397516083	P	42,807	9.21E−06
v15	g.47346378C>T	g.47367929C>T	c.927−8G>A	i11	1	0.010	0.11	pRi11/E12ext	Frameshift—PTC	⁵²	rs1468812059	NA	NA	NA
v16	g.47345754G>A	g.47367305G>A	c.1090+453C>T	i12	0	0	0.56	crypEins in i12	Frameshift—PTC	^15,19	rs2095893477	LP	870,077	NA
v17	g.47344199T>G	g.47365750T>G	c.1091−575A>C	i12	0	0	0.38	crypEins in i12	Frameshift—PTC	¹⁵	NA	NA	NA	NA
v18	g.47343342C>T	g.47364893C>T	c.1224−80G>A	i13	6	0.175	0.94	pRi13/E14ext	In-frame (ins 26 aa)	¹⁶	rs1025692267	LP	693,982	NA
v19	g.47343314C>T	g.47364865C>T	c.1224−52G>A	i13	12	0.125	0.99	pRi13/E14ext	Frameshift—PTC	^15,53	rs786204336	LP/P	188,544	3.19E−05
v20	g.47343283T>C	g.47364834T>C	c.1224−21A>G	i13	0	0	0.90	pRi13/E14ext	Frameshift—PTC	^14,54	NA	US	1,180,864	NA
v21	g.47343281C>T	g.47364832C>T	c.1224−19G>A	i13	15	0.156	0.81	pRi13/E14ext	Frameshift—PTC	⁴⁹	rs587776699	LP	138,326	2.56E−05
v22	g.47343159G>T	g.47364710G>T	c.1227−14C>A	i14	0	0	0.43	E15sk	Frameshift—PTC	²¹	rs574567658	NA	NA	4.20E−06
v23	g.47343158C>T	g.47364709C>T	c.1227−13G>A	i14	8	0.083	0.98	pRi14/E15ext	Frameshift—PTC	^21,55	rs397515893	US/P	42,513	1.48E−05
v24	g.47343154G>T	g.47364705G>T	c.1227−9C>A	i14	0	0	0.08	E15sk	Frameshift—PTC	²¹	rs11570079	US	921,244	4.17E−06
v25	g.47342827C>G	g.47364378C>G	c.1457+3G>C	i16	0	0	0.25	E16sk	Frameshift—PTC	²¹	rs112918360	NA	NA	NA
v26	g.47342825C>G	g.47364376C>G	c.1457+5G>C	i16	1	0.010	0.93	E16sk	Frameshift—PTC	^14,21	rs727503202	US	164,116	NA
v27	g.47342574T>A	g.47364125T>A	c.1624+4A>T	i17	3	0.031	0.16	E17sk	Stop gain—PTC	^14,17,21,51	rs397515916	P	42,556	1.33E−05
v28	g.47342163G>T	g.47363714G>T	c.1625−7C>A	i17	0	0	0.11	E18sk	Frameshift—PTC	²¹	rs760972720	NA	NA	1.07E−05
v29	g.47341986C>T	g.47363537C>T	c.1790+5G>A	i18	0	0	0.89	E18sk	Frameshift—PTC	²¹	rs727504489	US	178,851	NA
v30	g.47341133C>T	g.47362684C>T	c.1897+5G>A	i19	0	0	0.77	E19sk	Frameshift—PTC	²¹	rs397515936	US	42,583	NA
v31	g.47341055T>C	g.47362606T>C	c.1898−23A>G	i19	4	0.042	0.04	cRi19	Frameshift—PTC	¹⁸	rs1158983908	NA	NA	5.01E−06
v32	g.47340403G>A	g.47361954G>A	c.1927+600C>T	i20	7	0.204	0.13	crypEins in i20	Frameshift—PTC	¹⁶	rs1595845204	P	692,114	NA
v33	g.47340359C>A	g.47361910C>A	c.1928−569G>T	i20	0	0	0.23	crypEins in i20	Frameshift—PTC	¹⁹	rs1343555574	NA	NA	NA
v34	g.47338682G>C	g.47360233G>C	c.2149−3C>G	i22	1	0.010	0.61	E23sk	Frameshift—PTC	²¹	rs113182334	NA	NA	NA
v35	g.47338517C>G	g.47360068C>G	c.2308+3G>C	i23	0	0	0.74	E23sk	Frameshift—PTC	⁵⁶	NA	NA	NA	NA
v36	g.47337820T>C	g.47359371T>C	c.2309−26A>G	i23	0	0	0.35	E24sk	In-frame (del 35 aa)	³	rs886041030	P	8610	NA
v37	g.47337615C>A	g.47359166C>A	c.2414−36G>T	i24	0	0	0.52	pRi24/E25ext	Frameshift—PTC	⁴⁸	rs371970979	NA	NA	8.07E−06
v38	g.47335212G>C	g.47356763G>C	c.2738−3C>G	i26	0	0	0.61	E27sk	Stop gain—PTC	²¹	NA	NA	NA	NA
v39	g.47335037C>A	g.47356588C>A	c.2905+5G>T	i27	0	0	0.96	E27sk	Stop gain—PTC	²¹	rs193922381	US/LP	42,668	NA
v40	g.47333552C>T	g.47355103C>T	c.3190+5G>A	i29	10	0.104	0.85	E29sk	Frameshift—PTC	^21,50	rs587782958	P	155,808	1.68E−05
v41	g.47333189C>A	g.47354740C>A	c.3330+5G>T	i30	0	0	0.25	E30sk	Frameshift—PTC	²¹	rs373746463	P/LP	42,707	NA
v42	g.47333189C>G	g.47354740C>G	c.3330+5G>C	i30	14	0.146	0.30	E30sk	Frameshift—PTC	^2,21	rs373746463	P/LP	42,706	2.71E−05
v43	g.47333189C>T	g.47354740C>T	c.3330+5G>A	i30	1	0.010	0.25	E30sk	Frameshift—PTC	²¹	rs373746463	P	8602	7.74E−06
v44	g.47332999A>C	g.47354550A>C	c.3331−26T>G	i30	3	0.031	0.16	cRi30	Frameshift—PTC	^{This study}	NA	NA	NA	NA
v45	g.47332705G>C	g.47354256G>C	c.3491−3C>G	i31	4	0.042	0.90	E32sk	Frameshift—PTC	¹⁷	rs730880592	LP/US	181,010	NA
v46	g.47332270G>C	g.47353821G>C	c.3628−12C>G	i32	0	0	0.95	E33sk	Frameshift—stop loss	²¹	rs371428751	NA	NA	4.02E−06

vID—ID number assigned to each variant. Genomic (GRCh38 and Grch37 assembly versions) and coding DNA Reference Sequences to name the variants are indicated. L—variant location, intron (i) number. HCM—number (n) and percentage (%) of HCM probands in the HIC cohort database carrying each variant. HCM percentages for variants located up to 50–60 nucleotides from the splice site, are relative to 9,611 HCM probands tested by massively parallel sequencing in which intronic flanking regions were covered; HCM percentages for deep intronic variants are relative to 3,437 HCM probands tested by massively parallel sequencing in which all introns of MYBPC3 were covered. Twenty-five variants were identified in 122 probands (sum of all n values) with HCM. With a few exceptions, most variants were detected only in HCM probands but not in patients with other inherited cardiovascular diseases (12,112 probands with intronic flanking regions sequenced, and 4,505 probands with complete MYBPC3 intronic regions sequenced). Six variants were also detected in seven patients with other phenotypes, as follows: v1 was detected also in a case of Marfan syndrome; v2 in two cases of sudden cardiac death and dilated cardiomyopathy/myocarditis, respectively; v14 was detected in a patient with hyperlipoproteinemia; v19 and v32 in two cases of sudden cardiac death; and v42 in one case of dilated cardiomyopathy.
SpliceAI Δ score maximum SpliceAI Δ score, Splicing defect aberrant transcript structure reported in the corresponding references (Ref), the affected Exon (E) or intron (i) number is indicated, tr truncated, sk skipped, ext extended, complete (cRi) or partial (pRi) retention of intron, crypEins cryptic exon insertion, TRF translational reading frame, PTC premature termination codon, aa amino acids, del deletion, ins insertion, dbSNP ID accession number in dbSNP, NA not available, ClinVar ClinVar interpretation category, LB likely benign, P pathogenic, LP likely pathogenic, US uncertain significance, ClinVar ID accession number in ClinVar, gnomAD frequency of the alternative allele in gnomAD.

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Table 1 Frequency of cryptic splice-altering MYBPC3 variants in a large cohort of HCM probands.

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