rs111033451
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004004.6(GJB2):c.19C>T(p.Gln7Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,856 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q7Q) has been classified as Likely benign.
Frequency
Consequence
NM_004004.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.19C>T | p.Gln7Ter | stop_gained | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.19C>T | p.Gln7Ter | stop_gained | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.19C>T | p.Gln7Ter | stop_gained | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.19C>T | p.Gln7Ter | stop_gained | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249370Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134976
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727224
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 11, 2016 | Variant summary: The c.19C>T variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.269dupT/p.Val91fsX11, c.334_335delAA/p.Lys112fsX2). One in-silico tool predicts damaging outcome for this variant. This variant has been reported predominantly in Ecuadorian population in patients with syndromic or non-syndromic hearing loss. This variant is not found in 121382 control chromosomes. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 21, 2015 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | This sequence change creates a premature translational stop signal (p.Gln7*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 220 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033451, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with GJB2-related conditions (PMID: 12865758, 25085072, 31370293). ClinVar contains an entry for this variant (Variation ID: 44728). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys202*) have been determined to be pathogenic (PMID: 23141775). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2021 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 220 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27535533, 25085072, 12865758, 31370293) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 02, 2017 | - - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 18, 2009 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at