chr13-20189048-CACAGTGTTGGG-C
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004004.6(GJB2):βc.523_533delβ(p.Pro175GlyfsTer31) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 32)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
GJB2
NM_004004.6 frameshift
NM_004004.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.94
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 45 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-20189048-CACAGTGTTGGG-C is Pathogenic according to our data. Variant chr13-20189048-CACAGTGTTGGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 228350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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GJB2 | NM_004004.6 | c.523_533del | p.Pro175GlyfsTer31 | frameshift_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.523_533del | p.Pro175GlyfsTer31 | frameshift_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.523_533del | p.Pro175GlyfsTer31 | frameshift_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.523_533del | p.Pro175GlyfsTer31 | frameshift_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251298Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135838
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461822Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727202
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74332
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change creates a premature translational stop signal (p.Pro175Glyfs*31) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) of the GJB2 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 228350). This variant has not been reported in the literature in individuals affected with GJB2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 07, 2016 | The p.Pro175fs variant in GJB2 has not been previously reported in individuals w ith hearing loss. This variant was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 175 and leads to a premature termination codon 31 amino acids downstream. This alteration is then predicted to lead to a truncate d or unstable protein. In summary, this variant meets the criteria to be classif ied as pathogenic for autosomal recessive hearing loss based on the predicted im pact of the variant. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at