rs200104362

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1PP2BP4_Strong

The NM_004004.6(GJB2):c.503A>G(p.Lys168Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,060 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K168K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000052 ( 1 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 7.97

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

Bart-Pumphrey syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
ichthyosis, hystrix-like, with hearing loss
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
keratoderma hereditarium mutilans
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
palmoplantar keratoderma-deafness syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
autosomal recessive nonsyndromic hearing loss 1A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
autosomal dominant keratitis-ichthyosis-hearing loss syndrome
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
autosomal dominant nonsyndromic hearing loss 3A
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
KID syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GJB2 links:

ENSG00000296095 (HGNC:):

ENSG00000296095 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_004004.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 111 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: -0.72044 (below the threshold of 3.09). Trascript score misZ: 0.4379 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 1A, ichthyosis, hystrix-like, with hearing loss, keratoderma hereditarium mutilans, hearing loss, autosomal recessive, Bart-Pumphrey syndrome, palmoplantar keratoderma-deafness syndrome, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss, KID syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.031392753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.503A>G	p.Lys168Arg	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 link	c.503A>G	p.Lys168Arg	missense_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GJB2	ENST00000382848.5 link	c.503A>G	p.Lys168Arg	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2 link	c.503A>G	p.Lys168Arg	missense_variant	Exon 1 of 1	6		ENSP00000372295.1
ENSG00000296095	ENST00000736390.1 link	n.232-3499A>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

101

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00570

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:

0.00382

GnomAD2 exomes

AF:

0.0000518

AC:

AN:

251060

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000961

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112006

Other (OTH)

AF:

0.000464

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152302

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41568

American (AMR)

AF:

0.00569

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000977

Hom.:

Bravo

AF:

0.00128

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

May 09, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in several unrelated patients with apparently non-syndromic hearing loss in the published literature, often as a single heterozygous variant (PMID: 17357124, 19125024, 20497192, 21728791, 23684175, 29773520); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19283857, 20022641, 30245029, 25262649, 17357124, 25388846, 17567889, 19125024, 20497192, 23684175, 21728791, 32387678, 19230829, 33096615, 24156272, 20381175, 24158611, 17666888, 19887791, 19081147, 29773520, 36048236) -

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 168 of the GJB2 protein (p.Lys168Arg). This variant is present in population databases (rs200104362, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of GJB2-related conditions (PMID: 17357124, 21728791, 23684175). ClinVar contains an entry for this variant (Variation ID: 44756). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 80%. 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. -

Dec 12, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2Benign:1

Nov 18, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Lys168Arg variant in GJB2 has been previously reported in >20 individuals with hearing loss, primarily of Brazilian or Latino ancestry (Batisscoco 2009, Christiani 2007, Dalamon 2013, Felix 2019, Fischer 2009, Gravina 2010, Manzoli 2013, Martins 2013, Putcha 2007, Samanich 2007, Shan 2010, Tsukada 2010). However, the variant has not been reported in the homozygous or compound heterozygous state. It has been identified in 0.03% (10/35418) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, the computational data and the fact that none of the probands had a second variant identified on the other copy of the gene suggests that the variant is more likely benign. ACMG/AMP criteria applied: PM2_Supporting, BP4. -

Dec 29, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GJB2 c.503A>G (p.Lys168Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 152268 control chromosomes, predominantly at a frequency of 0.0057 within the Latino subpopulation in the gnomAD v3.1.1 database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 17-fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss phenotype (0.00034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.503A>G has been reported in the literature in the heterozygous state without any other GJB2 pathogenic variants in individuals affected with Non-Syndromic Hearing Loss (e.g. Christiani_2007, Putcha_2007, Samanich_2007, Batissoco_2009, Tsukada_2010, da Silva-Costa_2011, Dalamon_2013, Felix_2019, Figueroa-Ildefonso_2019, Buonfiglio_2020) but it was also reported in unaffected/control individuals (e.g. Samanich_2007, da Silva-Costa_2011). These reports do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. However, c.503A>G was expert-curated as Likely benign in the Deafness Variation Database (Azaiez_2018). Based on the evidence outlined above, the variant was classified as likely benign. -

Nov 11, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GJB2 c.503A>G; p.Lys168Arg variant (rs200104362) has been reported in multiple individuals in hearing loss cohorts; however, inheritance and specific clinical information were not provided for these individuals (Batissoco 2009, Manzoli 2013, Samanich 2007, Shearer 2014). The p.Lys168Arg variant is reported in ClinVar (Variant ID: 44756) and is found in the general population with an overall allele frequency of 0.005% (15/282,470 alleles) in the Genome Aggregation Database. The lysine at codon 168 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Given the lack of clinical and functional data, the significance of the p.Lys168Arg variant is uncertain at this time. References: Batissoco et al. Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling. Ear Hear. 2009 Feb;30(1):1-7. doi: 10.1097/AUD.0b013e31819144ad. Manzoli et al. Non-syndromic hearing impairment in a multi-ethnic population of Northeastern Brazil. Int J Pediatr Otorhinolaryngol. 2013 Jul;77(7):1077-82. doi: 10.1016/j.ijporl.2013.04.001. Epub 2013 May 15. Samanich et al. Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment. Am J Med Genet A. 2007 Apr 15;143A(8):830-8. Shearer et al. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet. 2014 Oct 2;95(4):445-53. doi: 10.1016/j.ajhg.2014.09.001. Epub 2014 Sep 25. -

Autosomal recessive nonsyndromic hearing loss 1A

Uncertain:1

May 09, 2017

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nonsyndromic genetic hearing loss

Uncertain:1

Aug 31, 2020

INGEBI, INGEBI / CONICET

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.503A>G, p.(Lys168Arg) variant in GJB2 gene is 0,015% (10/35418 Latino alleles with 95%CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) which meets the criteria to apply to PM2_Supporting rule. Computational evidence predicted a pathogenic effect of the mutation to the protein (REVELscore: 0.720) applying to PP3 criteria. The p.(Lys168Arg) change has been identified only in heterozygous state in several patients (PMID: 17567889, 19125024, 20381175, 20497192, 21728791, 24156272, 19887791). Therefore, the clinical significance of this variant is currently uncertain (PM2_Supporting, PP3). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;D;D

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

.;.;T

MetaRNN

Benign

0.031

T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

2.0

M;M;M

PhyloP100

8.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

N;N;.

REVEL

Pathogenic

0.72

Sift

Benign

0.24

T;T;.

Sift4G

Benign

0.31

T;T;.

Polyphen

0.074

B;B;B

Vest4

0.55

MVP

0.91

MPC

0.048

ClinPred

0.19

GERP RS

5.5

Varity_R

0.42

gMVP

0.84

Mutation Taster

=61/39

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over