NM_004004.6:c.79G>A

Variant names:

• chr13-20189503-C-T
• rs2274084
• NM_004004.6:c.79G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_004004.6(GJB2):​c.79G>A​(p.Val27Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0184 in 1,614,144 control chromosomes in the GnomAD database, including 4,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (418 hom., cov: 32)
  • Exomes 𝑓: 0.018 (3603 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 6.12
• Publications: 160 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: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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=0.0041432083).
• BP6: Variant 13-20189503-C-T is Benign according to our data. Variant chr13-20189503-C-T is described in ClinVar as Benign. ClinVar VariationId is 36279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.79G>A	p.Val27Ile	missense	Exon 2 of 2	NP_003995.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	ENST00000382848.5	TSL:1 MANE Select	c.79G>A	p.Val27Ile	missense	Exon 2 of 2	ENSP00000372299.4
	GJB2	ENST00000382844.2	TSL:6	c.79G>A	p.Val27Ile	missense	Exon 1 of 1	ENSP00000372295.1
	GJB2	ENST00000906230.1		c.79G>A	p.Val27Ile	missense	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3943 AN: 152180 Hom.: 419 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0540 AC: 13514 AN: 250230 AF XY: 0.0444

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.277

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.0331

GnomAD4 exome AF: 0.0176 AC: 25688 AN: 1461846 Hom.: 3603 Cov.: 33 AF XY: 0.0164 AC XY: 11950 AN XY: 727222

African (AFR) AF: 0.00221 AC: 74 AN: 33480

American (AMR) AF: 0.213 AC: 9506 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 439 AN: 26134

East Asian (EAS) AF: 0.334 AC: 13262 AN: 39700

South Asian (SAS) AF: 0.00693 AC: 598 AN: 86254

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53420

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000725 AC: 806 AN: 1111970

Other (OTH) AF: 0.0162 AC: 976 AN: 60396

GnomAD4 genome AF: 0.0259 AC: 3949 AN: 152298 Hom.: 418 Cov.: 32 AF XY: 0.0308 AC XY: 2293 AN XY: 74480

African (AFR) AF: 0.00397 AC: 165 AN: 41578

American (AMR) AF: 0.137 AC: 2090 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.282 AC: 1455 AN: 5164

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68038

Other (OTH) AF: 0.0203 AC: 43 AN: 2114

Alfa AF: 0.0175 Hom.: 1305

Bravo AF: 0.0393

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.0454 AC: 5509

Asia WGS AF: 0.0980 AC: 342 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	Autosomal recessive nonsyndromic hearing loss 1A (5)
-	-	4	not provided (4)
-	-	2	Autosomal dominant nonsyndromic hearing loss 3A (2)
-	-	1	Ichthyosis, hystrix-like, with hearing loss (1)
-	-	1	Nonsyndromic genetic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.8	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.57
Sift	Benign	0.19	T
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.15
MPC		0.060
ClinPred		0.053	T
GERP RS		5.2
PromoterAI		0.0013	Neutral
Varity_R		0.59
gMVP		0.83
Mutation Taster		=49/51	polymorphism (auto)

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: rs2274084; hg19: chr13-20763642; COSMIC: COSV67010703; COSMIC: COSV67010703;