rs111033401

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_004004.6(GJB2):​c.9G>T​(p.Trp3Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W3S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

GJB2
NM_004004.6 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.75

Publications

14 publications found
Variant links:
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

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1
In a chain Gap junction beta-2 protein (size 225) in uniprot entity CXB2_HUMAN there are 157 pathogenic changes around while only 18 benign (90%) in NM_004004.6
PM2
Very rare variant in population databases, with high coverage;
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GJB2NM_004004.6 linkc.9G>T p.Trp3Cys missense_variant Exon 2 of 2 ENST00000382848.5 NP_003995.2 P29033H9U1J4
GJB2XM_011535049.3 linkc.9G>T p.Trp3Cys missense_variant Exon 2 of 2 XP_011533351.1 P29033H9U1J4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJB2ENST00000382848.5 linkc.9G>T p.Trp3Cys missense_variant Exon 2 of 2 1 NM_004004.6 ENSP00000372299.4 P29033
GJB2ENST00000382844.2 linkc.9G>T p.Trp3Cys missense_variant Exon 1 of 1 6 ENSP00000372295.1 P29033
ENSG00000296095ENST00000736390.1 linkn.232-3993G>T intron_variant Intron 1 of 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 07, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: GJB2 c.9G>T (p.Trp3Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249290 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.9G>T in individuals affected with Non-Syndromic Hearing Loss and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1
Nov 27, 2020
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.57
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
D;D;D
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
.;.;D
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.7
H;H;H
PhyloP100
7.7
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-12
D;D;.
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D;.
Sift4G
Pathogenic
0.0
D;D;.
Polyphen
1.0
D;D;D
Vest4
0.92
MutPred
0.84
Gain of catalytic residue at M1 (P = 0.0014);Gain of catalytic residue at M1 (P = 0.0014);Gain of catalytic residue at M1 (P = 0.0014);
MVP
0.99
MPC
0.33
ClinPred
1.0
D
GERP RS
4.5
PromoterAI
0.010
Neutral
Varity_R
0.97
gMVP
0.99
Mutation Taster
=39/61
disease causing

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

Publications

Other links and lift over

dbSNP: rs111033401; hg19: chr13-20763712; API