rs111033186

Variant names:

• chr13-20189125-C-T
• rs111033186
• NM_004004.6:c.457G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-20189125-C-T
• chr13-20189125-C-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.457G>A​(p.Val153Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,614,130 control chromosomes in the GnomAD database, including 206 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. V153A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (198 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:21
• Conservation: PhyloP100: 0.240
• Publications: 82 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: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 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 dominant nonsyndromic hearing loss 3A, ichthyosis, hystrix-like, with hearing loss, autosomal recessive nonsyndromic hearing loss 1A, nonsyndromic genetic hearing loss, palmoplantar keratoderma-deafness syndrome, keratoderma hereditarium mutilans, Bart-Pumphrey syndrome, KID syndrome, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, autosomal dominant nonsyndromic hearing loss, hearing loss, autosomal recessive, syndromic genetic hearing loss.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035775304).
• BP6: Variant 13-20189125-C-T is Benign according to our data. Variant chr13-20189125-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0519 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.457G>A	p.Val153Ile	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.457G>A	p.Val153Ile	missense	Exon 2 of 2	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.457G>A	p.Val153Ile	missense	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.457G>A	p.Val153Ile	missense	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 623 AN: 152218 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0537

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00925 AC: 2324 AN: 251112 AF XY: 0.0117

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.00364

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00561 AC: 8203 AN: 1461794 Hom.: 198 Cov.: 33 AF XY: 0.00733 AC XY: 5333 AN XY: 727186

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.00148 AC: 66 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 328 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0532 AC: 4589 AN: 86256

European-Finnish (FIN) AF: 0.00236 AC: 126 AN: 53338

Middle Eastern (MID) AF: 0.0130 AC: 75 AN: 5768

European-Non Finnish (NFE) AF: 0.00234 AC: 2606 AN: 1111998

Other (OTH) AF: 0.00649 AC: 392 AN: 60394

GnomAD4 genome AF: 0.00409 AC: 623 AN: 152336 Hom.: 8 Cov.: 33 AF XY: 0.00490 AC XY: 365 AN XY: 74490

African (AFR) AF: 0.000241 AC: 10 AN: 41578

American (AMR) AF: 0.00183 AC: 28 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0537 AC: 259 AN: 4822

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00392 AC: 267 AN: 68042

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00417 Hom.: 9

Bravo AF: 0.00244

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.0105 AC: 1279

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00427

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Autosomal recessive nonsyndromic hearing loss 1A (4)
-	-	4	not provided (4)
-	-	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	-	-	Hearing loss, autosomal recessive (1)
-	-	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	0.074
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.76
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0036	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	-0.30	N
PhyloP100		0.24
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.21	N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.037
MPC		0.034
ClinPred		0.0017	T
GERP RS		5.5
Varity_R		0.12
gMVP		0.80
Mutation Taster		=97/3	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: rs111033186; hg19: chr13-20763264;