rs2274083

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_004004.6(GJB2):​c.341A>T​(p.Glu114Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E114G) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

GJB2
NM_004004.6 missense

Scores

7
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.431
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a chain Gap junction beta-2 protein (size 225) in uniprot entity CXB2_HUMAN there are 70 pathogenic changes around while only 16 benign (81%) in NM_004004.6
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29956776).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GJB2NM_004004.6 linkc.341A>T p.Glu114Val missense_variant Exon 2 of 2 ENST00000382848.5 NP_003995.2 P29033H9U1J4
GJB2XM_011535049.3 linkc.341A>T p.Glu114Val 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.341A>T p.Glu114Val missense_variant Exon 2 of 2 1 NM_004004.6 ENSP00000372299.4 P29033
GJB2ENST00000382844.2 linkc.341A>T p.Glu114Val missense_variant Exon 1 of 1 6 ENSP00000372295.1 P29033

Frequencies

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Uncertain
0.62
D;D;D
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.37
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.79
.;.;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.30
T;T;T
MetaSVM
Uncertain
0.34
D
MutationAssessor
Benign
2.0
M;M;M
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.85
N;N;.
REVEL
Uncertain
0.43
Sift
Benign
0.051
T;T;.
Sift4G
Benign
0.071
T;T;.
Polyphen
0.14
B;B;B
Vest4
0.21
MutPred
0.54
Loss of disorder (P = 0.001);Loss of disorder (P = 0.001);Loss of disorder (P = 0.001);
MVP
0.96
MPC
0.059
ClinPred
0.20
T
GERP RS
5.3
Varity_R
0.19
gMVP
0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-20763380; API