rs772264564
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004004.6(GJB2):c.465T>A(p.Tyr155Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
GJB2
NM_004004.6 stop_gained
NM_004004.6 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: -0.230
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 62 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-20189117-A-T is Pathogenic according to our data. Variant chr13-20189117-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 195205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189117-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.465T>A | p.Tyr155Ter | stop_gained | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.465T>A | p.Tyr155Ter | stop_gained | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.465T>A | p.Tyr155Ter | stop_gained | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.465T>A | p.Tyr155Ter | stop_gained | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251140Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135764
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461800Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727186
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Payam Genetics Center, General Welfare Department of North Khorasan Province | Mar 01, 2023 | The GJB2 c.465T>A (p.Y155X) is a missens mutation and results at the protein level is a disfunctional or truncated protein, predicted lead to disease.This variant is not present in Iranian population databases. This variant as Pathogenic according to the ACMG classification. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 18, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2018 | The Y155X nonsense variant has been reported previously as compound heterozygous with other pathogenic variants in patients with autosomal recessive nonsyndromic hearing loss (DFNB1) (Tekin et al., 2005; Hismi et al., 2006; Bonyadi et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
D;D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at