chr13-20189217-T-A

Position:

chr13-20189217-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_004004.6(GJB2):c.365A>T(p.Lys122Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 4.04

Variant links:

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]

GJB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_004004.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 13-20189217-T-A is Pathogenic according to our data. Variant chr13-20189217-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.365A>T	p.Lys122Ile	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3 linkuse as main transcript	c.365A>T	p.Lys122Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.365A>T	p.Lys122Ile	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.365A>T	p.Lys122Ile	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000599

AC:

AN:

250324

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135428

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000335

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26275501, 25447126, 12865758, 10751669, 10376574, 25388846, 16125251, 22925408, 32003480, 17041943, 15365987, 11102979, 19235794, 17666888, 19081147, 18368581, 16222667, 12408072, 18776652, 10980526, 12067629, 26444186, 12457340, 30708180, 10704187, 31160754, 38855775, 34645491, 36048236) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 122 of the GJB2 protein (p.Lys122Ile). This variant is present in population databases (rs111033295, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of autosomal recessive nonsyndromic deafness (PMID: 10376574, 22925408, 31160754; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 44742). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 29, 2018	The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 01, 2016	Variant summary: The GJB2 c.365A>T (p.Lys122Ile) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 6/121646 control chromosomes at a frequency of 0.0000493, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). This variant has been identified in compound heterozygous state in patients with non-syndromic hearing loss, and is considered pathogenic in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 24, 2016	- -

Autosomal dominant nonsyndromic hearing loss 3A

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 24, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Nov 25, 2018	This variant was reported as pathogenic in the compound heterozygous state in patients with Deafness, autosomal recessive 1 (PMID: 25388846 and 10376574). This variant has also been previously reported as a heterozygous change in patients with hearing loss of an unspecified inheritance pattern (PMID: 12865758, 16222667, 17041943, 18776652). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0053% (13/245106) and thus is presumed to be rare. The c.365A>T (p.Lys122Ile) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.365A>T (p.Lys122Ile) variant is classified as pathogenic. -

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 02, 2019

The GJB2 c.365A>T; p.Lys122Ile (rs111033295) is reported in the literature in multiple individuals with hearing loss (de la Luz Arenas-Sordo 2012, Green 1999, Lee 2009, Naghavi 2008, Pandya 2007, Prasad 2000, Putcha 2007, Tang 2006), and it has been previously identified by our laboratory in several patients who were referred for hearing loss. Several affected individuals were found to carry an additional pathogenic variant (de la Luz Arenas-Sordo 2012, Lee 2009, Putcha 2007). The p.Lys122Ile variant is classified as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variant ID: 44742) and it is found in the Latino population with an overall allele frequency of 0.04% (15/34582 alleles) in the Genome Aggregation Database. The lysine at codon 122 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on the available information, the p.Lys122Ile variant is classified as likely pathogenic. References: de la Luz Arenas-Sordo et al. Unique spectrum of GJB2 mutations in Mexico. Int J Pediatr Otorhinolaryngol. 2012 Nov;76(11):1678-80. doi: 10.1016/j.ijporl.2012.08.005. Epub 2012 Aug 24. Green et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Lee et al. Audiologic and temporal bone imaging findings in patients with sensorineural hearing loss and GJB2 mutations. Laryngoscope. 2009 Mar;119(3):554-8. Naghavi et al. GJB2 mutations in Baluchi population. J Genet. 2008 Aug;87(2):195-7. Pandya et al. Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands. Genet Med. 2003 Jul-Aug;5(4):295-303. Prasad et al. Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). Hum Mutat. 2000 Dec;16(6):502-8. Putcha et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Tang et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006 Nov 15;140(22):2401-15. -

Hearing loss

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Dec 19, 2013

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.365A>T (p.K122I) alteration is located in exon 2 (coding exon 1) of the GJB2 gene. This alteration results from an A to T substitution at nucleotide position 365, causing the lysine (K) at amino acid position 122 to be replaced by an isoleucine (I)._x000D_ _x000D_ Based on the available evidence, the GJB2 c.365A>T (p.K122I) alteration is classified as pathogenic for autosomal recessive GJB2-related nonsyndromic hearing loss; however, its clinical significance for autosomal dominant GJB2-related nonsyndromic hearing loss and GJB2-related syndromic hearing loss with ectodermal involvement is unclear. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (15/250324) total alleles studied. The highest observed frequency was 0.043% (15/34582) of Latino alleles. This variant has been identified with a second GJB2 variant in multiple individuals with hearing loss (Green, 1999; Putcha, 2007; Lee, 2009; de la Luz Arenas-Sordo, 2012; Shen, 2019). This variant has also been reported in the absence of a second GJB2 alteration in multiple heterozygous individuals with hearing loss (Azaiez, 2004; Cheng, 2005; Tang, 2006; Naghavi, 2008; Tayoun, 2016). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Hearing impairment

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 13, 2012

The Lys122Ile variant in GJB2 has been reported in 18 probands with hearing loss and was absent from over 400 control samples (Green 1999, Pandya 2003, Tang 200 6, Naghavi 2008). Therefore, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

D;D;D

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

.;.;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.4

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.4

D;D;.

REVEL

Pathogenic

0.85

Sift

Benign

0.087

T;T;.

Sift4G

Uncertain

0.043

D;D;.

Polyphen

0.96

D;D;D

Vest4

0.46

MutPred

0.79

Loss of solvent accessibility (P = 0.0017);Loss of solvent accessibility (P = 0.0017);Loss of solvent accessibility (P = 0.0017);

MVP

0.99

MPC

0.31

ClinPred

0.79

GERP RS

4.3

Varity_R

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over