13-20189068-A-T

Variant names:

• chr13-20189068-A-T
• rs770330002
• NM_004004.6:c.514T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM5 PP2 PP5

The NM_004004.6(GJB2):​c.514T>A​(p.Trp172Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,776 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W172C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (1 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 7.40

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_004004.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189066-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 590799.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 palmoplantar keratoderma-deafness syndrome, autosomal dominant nonsyndromic hearing loss, ichthyosis, hystrix-like, with hearing loss, KID syndrome, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, keratoderma hereditarium mutilans, hearing loss, autosomal recessive, autosomal dominant nonsyndromic hearing loss 3A, Bart-Pumphrey syndrome, autosomal recessive nonsyndromic hearing loss 1A.
• PP5: Variant 13-20189068-A-T is Pathogenic according to our data. Variant chr13-20189068-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557805.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.514T>A	p.Trp172Arg	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.514T>A	p.Trp172Arg	missense_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.514T>A	p.Trp172Arg	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.514T>A	p.Trp172Arg	missense_variant	Exon 1 of 1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251118 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000479 AC: 7 AN: 1461776 Hom.: 1 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727182

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39692

Gnomad4 SAS exome AF: 0.0000812 AC: 7 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53324

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111998

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Jun 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 172 of the GJB2 protein (p.Trp172Arg). This variant is present in population databases (rs770330002, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 18941476). ClinVar contains an entry for this variant (Variation ID: 557805). 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. Experimental studies have shown that this missense change affects GJB2 function (PMID: 18941476). This variant disrupts the p.Trp172 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15790391, 20201936, 31195736). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 1A Uncertain:1

Apr 06, 2018

Counsyl

Significance: Uncertain significance

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Uncertain	0.69	D;D;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.63	.;.;T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.7	L;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	N;N;.
REVEL	Pathogenic	0.69
Sift	Benign	0.51	T;T;.
Sift4G	Benign	0.44	T;T;.
Polyphen		0.68	P;P;P
Vest4		0.89
MutPred		0.40		Gain of methylation at W172 (P = 0.0384);Gain of methylation at W172 (P = 0.0384);Gain of methylation at W172 (P = 0.0384);
MVP		0.91
MPC		0.22
ClinPred		0.54	D
GERP RS		5.7
Varity_R		0.76
gMVP		0.91
Mutation Taster		=44/56	disease causing

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: rs770330002; hg19: chr13-20763207;