13-20189071-C-T

Position:

• chr13-20189071-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_004004.6(GJB2):​c.511G>A​(p.Ala171Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 0.559

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 0 ACMG points.

• PM1: In a chain Gap junction beta-2 protein (size 225) in uniprot entity CXB2_HUMAN there are 70 pathogenic changes around while only 16 benign (81%) in NM_004004.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.110228986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.511G>A	p.Ala171Thr	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.511G>A	p.Ala171Thr	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.511G>A	p.Ala171Thr	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.511G>A	p.Ala171Thr	missense_variant	1/1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251052 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135728

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000269 AC: 393 AN: 1461756 Hom.: 0 Cov.: 33 AF XY: 0.000259 AC XY: 188 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74456

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000243 Hom.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2016	Variant classified as Uncertain Significance - Favor Benign. The p.Ala171Thr var iant in GJB2 has been previously reported in nine individuals with sensorineural hearing loss (Lin 2001, Najmabadi 2002, Wu 2002, Xiao 2004, Azaiez 2004, Putcha 2007, Samanich 2007, Han 2008, Bonyadi 2009, Bonyadi 2014, LMM data). However, a variant affecting the remaining copy of GJB2 was not identified in any of them . In addition, two individuals had cochlear malformations inconsistent with GJB 2-related hearing loss (Lin 2001, Wu 2002). One publication suggested that p.Ala 171Thr could be inherited in a dominant pattern (Xiao 2004); however, this is in consistent with findings from other studies. This variant has been identified i n two individuals with normal hearing (Samanich 2007, Han 2008) and has been ide ntified in 8/66556 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs201004645). Computational prediction tools and conservation analysis suggest that the p.Ala171Thr variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. In summary, while the clinical significance of the p.Ala171Thr vari ant is uncertain, these data suggest that it is more likely to be benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2023	Variant summary: GJB2 c.511G>A (p.Ala171Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251052 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (0.00013 vs 0.00034), allowing no conclusion about variant significance. c.511G>A has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (e.g. Wu_2002, Kashef_2015, Carranza_2016) and palmoplantar keratoderma (Harjama_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as benign, and five as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 26, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 171 of the GJB2 protein (p.Ala171Thr). This variant is present in population databases (rs201004645, gnomAD 0.02%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 11438992, 15603707). ClinVar contains an entry for this variant (Variation ID: 44758). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJB2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 27, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in at least one individual with clinical features associated with non-syndromic hearing loss. Computational tools predict that this variant is not damaging. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Uncertain	0.60	D;D;D
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.86	.;.;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Uncertain	-0.00060	T
MutationAssessor	Benign	1.4	L;L;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.45	N;N;.
REVEL	Uncertain	0.59
Sift	Benign	0.56	T;T;.
Sift4G	Benign	0.33	T;T;.
Polyphen		0.87	P;P;P
Vest4		0.14
MVP		0.84
MPC		0.039
ClinPred		0.023	T
GERP RS		2.9
Varity_R		0.14
gMVP		0.75

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: rs201004645; hg19: chr13-20763210; COSMIC: COSV67010506;