Table 2 Variant classification of the identified ESR2 variants

From: Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Variant

cDNA

Protein

Nucleotide conservation

Amino acid conservation

SIFT

PolyPhen2

MutationTaster

Grantham distance

Public databases

ACMG classification

1

c.541_543del (Hom)

p.(Asn181del)

/

Highly conserved: zebrafish

/

/

/

/

dbSNP: rs750091675ESP: 0.04%ExAC: 0.041%, no homozygous cases reportedgnomAD: 0.0368%, no homozygous cases reported

Class 4 (likely pathogenic) Criteria: ≥3 moderate pathogenic arguments (PM2, PM4, PM1, and PM3)19

2

c.251G>T (Het)

p.(Gly84Val)

Moderately conserved: phyloP: 4.22

Highly conserved: fruit fly

Tolerated

Probably damaging

Disease-causing

109

Absent in dbSNP, ESP, and ExACgnomAD: 0.000396% (singleton)

Class 4 (likely pathogenic)Criteria: ≥3 moderate pathogenic arguments (PM2, PM1, and PM6)19

3

c.1277T>G (Het)

p.(Leu426Arg)

Highly conserved: phyloP: 8.70N

Highly conserved: Tetraodon

Deleterious

Probably damaging

Disease-causing

102

Absent in dbSNP, ESP, ExAC, and gnomAD

Class 3 (uncertain significance)Criteria: classification criteria for classification as benign or pathogenic are not met (PM2, PM1, and PP3)19

  1. ACMG, American College of Medical Genetics and Genomics; dbSNP, Single Nucleotide Polymorphism database; ESP, Exome Sequencing Project; ExAC, Exome Aggregation Consortium; Het, heterozygous; Hom, homozygous; PM, moderate pathogenic criterion; PP, supporting pathogenic criterion.
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