Table 2 Characterisation of GJA8 variants identified in this study.

From: GJA8-associated developmental eye disorders: a new multicentre study highlights mutational hotspots and genotype-phenotype correlations

Genomic coordinates (hg38)

cDNA change

Aa change

Domain

Total MAF (gnomAD v4.1.0)

GERP + + _RS

Polyphen-2 HDIV

SIFT

CADD

Alpha-Missense

ACMG/AMP Classification

Previous studies with same variant

Chr1:147908019

c.64G>A

p.(Gly22Ser)

TM1

0

5.03

D (1.0)

D (0.0)

29.7

P (0.86)

Pathogenic (PS1, PS2, PM1, PM2, PP3)

[28, 30, 32]

Chr1:147908071

c.116C>T

p.(Thr39Met)

TM1

6.2E-7

4.9

D (1.0)

D (0.001)

28.8

A (0.63)

Uncertain significance (PM1, PM5, PP3)

N/A

Chr1:147908085

c.130G>A

p.(Val44Met)

ECL1

0

4.9

D (1.0)

D (0.01)

31

P (0.89)

Pathogenic (PS1, PM1, PM2, PP1, PP3)

[31, 29]

Chr1:147908151

c.196T>G

p.(Tyr66Asp)

ECL1

0

5.2

D (1.0)

D (0.0)

29.7

P (0.96)

Pathogenic (PS2, PM1, PM2, PM5, PP3)

N/A

Chr1:147908155

c.200A>G

p.(Asp67Gly)

ECL1

6.2E-7

5.2

D (1.0)

D (0.0)

26.4

P (0.94)

Pathogenic (PS1, PM1, PP3)

[17]

Chr1:147908181

c.226C>T

p.(Arg76Cys)

TM2

0

5.2

D (1.0)

D (0.001)

31

P (0.88)

Likely Pathogenic (PS1, PM1, PM2, PP3)

[17, 30]

Chr1:147908218

c.263C>T

p.(Pro88Leu)

TM2

0

5.2

D (1.0)

D (0.0)

32

P (0.92)

Pathogenic (PS1, PS2, PS3, PM1, PM2, PP3)

[35]

Chr1:147908235

c.280G>C

p.(Gly94Arg)

ICL

0

5.2

D (1.0)

D (0.001)

29.1

P (0.92)

Pathogenic (PS1, PM1, PM2, PM6, PP3)

[11,12,13, 33]

Chr1:147908236

c.281G>A

p.(Gly94Glu)

ICL

6.2E-7

5.2

D (1.0)

D (0.001)

27.5

P (0.95)

Pathogenic (PS1, PS3, PM1, PP1, PP3)

[12, 14]

Chr1:147908248

c.293A>G

p.(His98Arg)

ICL

0

5.2

D (1.0)

D (0.001)

24.2

A (0.65)

Pathogenic (PS1, PM1, PM2, PP1, PP3)

[32]

Chr1:147908520

c.565C>T

p.(Pro189Ser)

ECL2

0

4.89

D (1.0)

D (0.01)

27.6

P (0.87)

Pathogenic (PS1, PS2, PM1, PM2, PP3)

[27]

Chr1:147908547

c.592C>T

p.(Arg198Trp)

ECL2

0

2.7

D (1.0)

D (0.0)

26.7

P (0.92)

Pathogenic (PS1, PM1, PM2, PP1, PP3)

[30, 36]

  1. cDNA positions refer to NM_005267.5, the protein changes refer to NP_005258.2. Protein domains: NT N-terminal domain, TM transmembrane domain, ECL extracellular loop, ICL Intracellular loop, CT C-terminal domain. For each variant, total minor allele frequencies from gnomAD (v4.1.0) are reported. Conservation scores (GERP + + _RS) were retrieved from the dbNSFP database v4.7a (accessed in November 2024). GERP++_RS scores range from a minimum of −12.3 to a maximum of 6.17, and positions with scores ≥ 2 are considered conserved. In silico predictions of the functional effects of variants are reported for Polyphen-2, SIFT, CADD and AlphaMissense, retrieved from the dbNSFP database v4.7a (accessed in November 2024) (D Damaging, P Pathogenic, A Ambiguous). Variants were classified as ‘pathogenic’, ‘likely pathogenic’, or ‘uncertain significance’ based on the “ACGS Best Practice Guidelines for Variant Classification in Rare Disease” [23], an updated version of the ACMG/AMP guidelines [24]. N/A information not available.
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