NM_004004.6:c.132G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_004004.6(GJB2):c.132G>A(p.Trp44*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,176 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

GJB2
NM_004004.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.85

Publications

38 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 203 pathogenic variants in the truncated region.

PP5

Variant 13-20189450-C-T is Pathogenic according to our data. Variant chr13-20189450-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 158605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.132G>A	p.Trp44*	stop_gained	Exon 2 of 2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.132G>A	p.Trp44*	stop_gained	Exon 2 of 2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GJB2	ENST00000382848.5 link	c.132G>A	p.Trp44*	stop_gained	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4	P29033
GJB2	ENST00000382844.2 link	c.132G>A	p.Trp44*	stop_gained	Exon 1 of 1	6		ENSP00000372295.1	P29033
ENSG00000296095	ENST00000736390.1 link	n.232-3870G>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

250944

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1460884

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726532

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1111164

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.0000788

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41572

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

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:

0.0000712

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:4

Dec 24, 2021

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GJB2 c.132G>A (p.Trp44X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.5e-05 in 258564 control chromosomes. c.132G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (example, Green_1999, Prasad_2000, Snoeckx_2005, Roux_2004, Tang_2006, Putcha_2007, Lin_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 06, 2015

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Genomics and Human Genetics Laboratory, Pasteur Institut of Morocco

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:4

May 09, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GJB2 c.132G>A; p.Trp44Ter variant (rs104894407) has been reported in the literature in individuals with hearing loss who carried a pathogenic variant on the opposite chromosome (Green 1999, Martinez-Saucedo 2015, Roux 2004). It is reported in ClinVar (Variation ID: 158605), and observed in the general population databases at a frequency of 0.003 percent (8/276604 alleles; Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript, and is considered pathogenic. REFERENCES Link to ClinVar database for p.Trp44Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/158605/ Green GE et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Martinez-Saucedo M et al. Two novel compound heterozygous families with a trimutation in the GJB2 gene causing sensorineural hearing loss. Int J Pediatr Otorhinolaryngol. 2015 Dec;79(12):2295-9. Roux AF et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004 Mar 6;5:5. -

Dec 16, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a pathogenic variant in additional unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Green et al., 1999; Roux et al., 2004; Angeli et al., 2008); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 183 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 17666888, 26553399, 18758381, 10376574, 31589614, 15070423, 26346709, 17041943, 34440441) -

Jun 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Trp44*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894407, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 10376574, 15070423, 26346709, 26553399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 158605). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Leu56Argfs*26) have been determined to be pathogenic (PMID: 15967879, 16380907, 21465647, 22695344, 24158611). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hearing impairment

Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.97

PhyloP100

7.9

Vest4

0.87

GERP RS

5.2

PromoterAI

-0.031

Neutral

(source)

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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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