13-20188905-A-T

Position:

• chr13-20188905-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_004004.6:c.677T>A variant in GJB2 is a missense variant predicted to cause substitution of valine by aspartic acid at amino acid 226 (p.Val226Asp). The variant was absent from gnomAD v2.1.1 meeting PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.57 (PP3/BP4 not met). This variant has been identified in a heterozygous state in one individual with sensorineural hearing loss (PMID:20201936). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive nonsyndromic hearing loss. ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 8/22/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA387460663/MONDO:0019497/005

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 2.04

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.677T>A	p.Val226Asp	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.677T>A	p.Val226Asp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.677T>A	p.Val226Asp	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.677T>A	p.Val226Asp	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460126 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Nonsyndromic genetic hearing loss Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Aug 22, 2023

The NM_004004.6:c.677T>A variant in GJB2 is a missense variant predicted to cause substitution of valine by aspartic acid at amino acid 226 (p.Val226Asp). The variant was absent from gnomAD v2.1.1 meeting PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.57 (PP3/BP4 not met). This variant has been identified in a heterozygous state in one individual with sensorineural hearing loss (PMID: 20201936). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive nonsyndromic hearing loss. ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 8/22/2023). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.60	N;N;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.88	P;P;P
Vest4		0.60
MutPred		0.82		Loss of MoRF binding (P = 0.0211);Loss of MoRF binding (P = 0.0211);Loss of MoRF binding (P = 0.0211);
MVP		0.59
MPC		0.058
ClinPred		0.45	T
GERP RS		4.8
Varity_R		0.38
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs773846324; hg19: chr13-20763044;