13-20189241-T-C

Variant names:

• chr13-20189241-T-C
• rs2274083
• NM_004004.6:c.341A>G

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.341A>G​(p.Glu114Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,613,590 control chromosomes in the GnomAD database, including 688 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E114K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0069 (93 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (595 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.431
• Publications: 113 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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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=0.0017281473).
• BP6: Variant 13-20189241-T-C is Benign according to our data. Variant chr13-20189241-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.169 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.341A>G	p.Glu114Gly	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.341A>G	p.Glu114Gly	missense	Exon 2 of 2	ENSP00000372299.4
	GJB2	ENST00000382844.2	TSL:6	c.341A>G	p.Glu114Gly	missense	Exon 1 of 1	ENSP00000372295.1
	GJB2	ENST00000906230.1		c.341A>G	p.Glu114Gly	missense	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.00696 AC: 1059 AN: 152180 Hom.: 95 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.0149 AC: 3740 AN: 250202 AF XY: 0.0139

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.0000475

Gnomad NFE exome AF: 0.000530

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00545 AC: 7957 AN: 1461292 Hom.: 595 Cov.: 33 AF XY: 0.00533 AC XY: 3875 AN XY: 726944

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 365 AN: 26136

East Asian (EAS) AF: 0.167 AC: 6629 AN: 39700

South Asian (SAS) AF: 0.00381 AC: 329 AN: 86258

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52832

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000227 AC: 252 AN: 1112002

Other (OTH) AF: 0.00601 AC: 363 AN: 60392

GnomAD4 genome AF: 0.00693 AC: 1055 AN: 152298 Hom.: 93 Cov.: 33 AF XY: 0.00830 AC XY: 618 AN XY: 74480

African (AFR) AF: 0.000144 AC: 6 AN: 41570

American (AMR) AF: 0.000327 AC: 5 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.178 AC: 922 AN: 5166

South Asian (SAS) AF: 0.00953 AC: 46 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68024

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00154 Hom.: 16

Bravo AF: 0.0101

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0146 AC: 1768

Asia WGS AF: 0.0490 AC: 170 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	Autosomal recessive nonsyndromic hearing loss 1A (5)
-	-	5	not provided (5)
-	-	2	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;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A (1)
-	-	1	Ichthyosis, hystrix-like, with hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.43
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.28
Sift	Benign	0.23	T
Sift4G	Benign	0.25	T
Polyphen		0.0010	B
Vest4		0.028
MPC		0.043
ClinPred		0.026	T
GERP RS		5.3
Varity_R		0.17
gMVP		0.87
Mutation Taster		=79/21	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: rs2274083; hg19: chr13-20763380; COSMIC: COSV67010838;