chr13-20189481-A-G

Variant names:

• chr13-20189481-A-G
• rs35887622
• NM_004004.6:c.101T>C

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4 PP3 PP1 PM3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 510/25108) of the c.101T>C (p.Met34Thr) variant in the GJB2 gene is 1.46% for European (non-Finnish) genomes in gnomAD. This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID:31160754). This study also reported the variant in 27 homozygous affected probands, 17 affected probands with the p.Val37Ile variant in trans, 138 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans (PM3; PMID 31160754). The REVEL computational prediction analysis tool produced a score of 0.702, which is above the threshold necessary to apply PP3. Most dye transfer and electrical coupling assays support that the variant impacts protein function (PMID:16849369, 12189493, 10556284, 16300957, 15033936, 12189493); however, some assays showed partial function (PMID:27884957), and therefore this evidence was not counted. At least 16 segregations of the p.Met34Thr variant in family members have been described (PP1_Strong, PMID:31160754, 10903123). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Met34Thr in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing lossbased on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA172206/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0094 (9 hom., cov: 33)
  • Exomes 𝑓: 0.012 (149 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:50 U:2 O:3
• Conservation: PhyloP100: 5.06
• Publications: 199 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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, G2P, Genomics England PanelApp
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• syndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004004.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.101T>C	p.Met34Thr	missense	Exon 2 of 2	NP_003995.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	ENST00000382848.5	TSL:1 MANE Select	c.101T>C	p.Met34Thr	missense	Exon 2 of 2	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.101T>C	p.Met34Thr	missense	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.101T>C	p.Met34Thr	missense	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.00942 AC: 1434 AN: 152234 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00868 AC: 2176 AN: 250736 AF XY: 0.00852

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00442

Gnomad ASJ exome AF: 0.00795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.0123 AC: 18002 AN: 1461676 Hom.: 149 Cov.: 33 AF XY: 0.0119 AC XY: 8668 AN XY: 727104

African (AFR) AF: 0.00206 AC: 69 AN: 33478

American (AMR) AF: 0.00452 AC: 202 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00842 AC: 220 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.0215 AC: 1151 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0140 AC: 15604 AN: 1111826

Other (OTH) AF: 0.0125 AC: 754 AN: 60390

GnomAD4 genome AF: 0.00941 AC: 1433 AN: 152352 Hom.: 9 Cov.: 33 AF XY: 0.00949 AC XY: 707 AN XY: 74496

African (AFR) AF: 0.00284 AC: 118 AN: 41596

American (AMR) AF: 0.00575 AC: 88 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0206 AC: 219 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0138 AC: 942 AN: 68036

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.0109 Hom.: 36

Bravo AF: 0.00745

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0129 AC: 111

ExAC AF: 0.00850 AC: 1032

EpiCase AF: 0.0118

EpiControl AF: 0.0114

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
23	1	-	Autosomal recessive nonsyndromic hearing loss 1A (25)
13	-	-	not provided (13)
2	-	-	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 (2)
2	-	-	Hearing impairment (2)
2	-	-	Nonsyndromic genetic hearing loss (2)
1	-	-	Autosomal dominant keratitis-ichthyosis-hearing loss syndrome (1)
1	-	-	Autosomal dominant nonsyndromic hearing loss 3A (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B (1)
1	-	-	GJB2-related disorder (1)
-	1	-	Hearing loss (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Nonsyndromic Deafness (1)
1	-	-	Rare genetic deafness (1)
1	-	-	See cases (1)
-	-	-	Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	-0.071
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.013	D
Polyphen		0.038	B
Vest4		0.78
MVP		0.84
MPC		0.055
ClinPred		0.031	T
GERP RS		5.2
PromoterAI		-0.0051	Neutral
Varity_R		0.75
gMVP		0.90
Mutation Taster		=21/79	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs35887622; hg19: chr13-20763620;