rs774518779
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_004004.6(GJB2):c.506G>A(p.Cys169Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,760 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: 0.0000041 ( 0 hom. )
Consequence
GJB2
NM_004004.6 missense
NM_004004.6 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 7.86
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 14 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
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 13-20189076-C-T is Pathogenic according to our data. Variant chr13-20189076-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.506G>A | p.Cys169Tyr | missense_variant | 2/2 | ENST00000382848.5 | NP_003995.2 | |
GJB2 | XM_011535049.3 | c.506G>A | p.Cys169Tyr | missense_variant | 2/2 | XP_011533351.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.506G>A | p.Cys169Tyr | missense_variant | 2/2 | 1 | NM_004004.6 | ENSP00000372299.4 | ||
GJB2 | ENST00000382844.2 | c.506G>A | p.Cys169Tyr | missense_variant | 1/1 | 6 | ENSP00000372295.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251060Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135736
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461760Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727166
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GnomAD4 genome Cov.: 33
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33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Diagnostics Department, Viafet Genomics Laboratory | Aug 23, 2021 | As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in 2 family members who are not affected with this condition. This variant has been identified in a homozygous state in several patients affected with hearing loss (PMIDs: 24551843 and 25628337). In addition, functional studies have revealed that this variant fails to form junctional channels in vitro despite being correctly targeted to the plasma membrane (PMID: 25628337). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 20, 2017 | Variant summary: The GJB2 c.506G>A (p.Cys169Tyr) variant involves the alteration of a conserved nucleotide. "Cys169 is one of the six extracellular cysteine residues which are conserved in all connexin isoforms. These six cysteines form three disulfide bridges, which are likely to play an important role in guiding the correct folding of the connexin protein and the docking of the two hexameric hemichannels in the extracellular region" via Zonta_2015. 4/4 in silico tools predict a damaging outcome. A functional study, Zonta_2015 supports these predictions and showed that the variant "At the cellular level, our results show that the mutant protein fails to form junctional channels in HeLa transfectants despite being correctly targeted to the plasma membrane. At the molecular level, this effect can be accounted for by disruption of the disulfide bridge that Cys169 forms with Cys64 in the wild-type structure (Cx26WT)." This variant was found in 2/121012 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). Multiple publications have cited the variant in homozygous affected individuals, in addition a heterozygous affected individual, which a second mutation was not indicated to have been found. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Uncertain significance, flagged submission | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2022 | Published functional studies demonstrate a damaging effect as the p.(C169Y) variant results in disruption of junction channel formation, and disrupts the disulfide bridge that typically forms between the C169 and C64 residues (Zonta et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24551843, 25388846, 15365987, 34354426, 22103400, 25628337) - |
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 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 2022 | The p.Cys169Tyr variant in GJB2 has been reported in three homozygous and two heterozygous individuals with hearing loss and segregated with disease in seven affected individuals from three families (Zonta 2015 PMID: 25628337, Birkenhäger 2014 PMID: 24551843, Azaiez 2004 PMID: 15365987, Mahfood 2021 PMID: 34354426). It has also been identified in 0.00176% (2/113464) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID 265481). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant disrupts one of six conserved cysteine residues that form intramolecular disulfide bonds and are critical for intercellular channel formation (Zonta 2015 PMID: 25628337, Birkenhäger 2014 PMID: 24551843, Dahl 1991 PMID: 1707811). In vitro functional studies provide some evidence that this variant impacts protein function by obliterating the formation of gap junction plaques at points of cell-to-cell contact (Zonta 2015 PMID: 25628337); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PP1_Strong; PM1; PM3; PM2_Supporting; PP3; PS3_Supporting. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;.
Polyphen
D;D;D
Vest4
MutPred
Loss of methylation at K168 (P = 0.0255);Loss of methylation at K168 (P = 0.0255);Loss of methylation at K168 (P = 0.0255);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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