NM_004004.6:c.109G>A

Variant names:

• chr13-20189473-C-T
• rs72474224
• NM_004004.6:c.109G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS4 PP1_Strong PM3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 143/1558, including 8 homozygous observations) of the c.109G>A (p.Val37Ile) variant in the GJB2 gene is 7.9% for East Asian 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 139 homozygous affected probands, 17 affected probands with the p.Met34Thr variant in trans, 131 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans. However, because the variant is also very frequent in the general population, this criteria has been applied at the strength of Moderate. (PM3; PMID:31160754). The p.Val37Ile variant in GJB2 has been reported to segregate with hearing loss in at least 21 family members (PP1_Strong; PMID:31160754). Although homozygous or compound heterozygous observations have been identified in individuals with normal hearing, it has been suggested that individuals with the p.Val37Ile variant lose hearing at ~1dB/year, suggesting an age-related penetrance (PMID:27308859). Furthermore, in dye transfer and electrical coupling assays, both functional studies have shown that the variant impacts protein function (PMID:26088551, 12505163, 16300957) and knock-in mouse model demonstrated that the p.Val37Ile variant leads to the phenotype. However, because the codon for p.Val37 in mouse (GTG) was different from that in human (GTT), c.109G>A in mouse would translate into p.Val37Met, and the dye transfer and coupling assays have limited validation and correlation with pathogenicity, neither was not counted as functional evidence. (PMID:27623246). 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.Val37Ile in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA172210/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0040 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (83 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:54 U:1 B:1 O:1
• Conservation: PhyloP100: 6.10
• Publications: 447 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: 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

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 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.

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.109G>A	p.Val37Ile	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.109G>A	p.Val37Ile	missense	Exon 2 of 2	ENSP00000372299.4
	GJB2	ENST00000382844.2	TSL:6	c.109G>A	p.Val37Ile	missense	Exon 1 of 1	ENSP00000372295.1
	GJB2	ENST00000906230.1		c.109G>A	p.Val37Ile	missense	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152178 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0705

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00772 AC: 1936 AN: 250766 AF XY: 0.00681

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00806

Gnomad EAS exome AF: 0.0827

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00237 AC: 3462 AN: 1461390 Hom.: 83 Cov.: 33 AF XY: 0.00222 AC XY: 1616 AN XY: 726914

African (AFR) AF: 0.000538 AC: 18 AN: 33476

American (AMR) AF: 0.00268 AC: 120 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00774 AC: 202 AN: 26112

East Asian (EAS) AF: 0.0415 AC: 1648 AN: 39686

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86238

European-Finnish (FIN) AF: 0.00167 AC: 89 AN: 53414

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.000858 AC: 954 AN: 1111596

Other (OTH) AF: 0.00679 AC: 410 AN: 60382

GnomAD4 genome AF: 0.00400 AC: 609 AN: 152296 Hom.: 18 Cov.: 33 AF XY: 0.00435 AC XY: 324 AN XY: 74470

African (AFR) AF: 0.000890 AC: 37 AN: 41554

American (AMR) AF: 0.00333 AC: 51 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.0707 AC: 365 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68028

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00360 Hom.: 34

Bravo AF: 0.00451

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00658 AC: 799

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
25	1	-	Autosomal recessive nonsyndromic hearing loss 1A (27)
13	-	-	not provided (13)
3	-	-	GJB2-related disorder (3)
3	-	-	Hearing impairment (3)
3	-	-	Nonsyndromic genetic hearing loss (3)
1	-	1	Autosomal dominant nonsyndromic hearing loss 3A (2)
1	-	-	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 (1)
1	-	-	Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B (1)
1	-	-	Hearing loss, autosomal recessive (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome (1)
1	-	-	Nonsyndromic Deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.82	N
REVEL	Pathogenic	0.66
Sift	Benign	0.72	T
Sift4G	Benign	0.51	T
Polyphen		1.0	D
Vest4		0.26
MVP		0.67
MPC		0.043
ClinPred		0.049	T
GERP RS		5.2
PromoterAI		0.0078	Neutral
Varity_R		0.42
gMVP		0.84
Mutation Taster		=57/43	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: rs72474224; hg19: chr13-20763612;