rs770116143
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_004004.6(GJB2):c.564_565delGA(p.Lys188AsnfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_004004.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.564_565delGA | p.Lys188AsnfsTer21 | frameshift_variant | Exon 2 of 2 | ENST00000382848.5 | NP_003995.2 | |
GJB2 | XM_011535049.3 | c.564_565delGA | p.Lys188AsnfsTer21 | frameshift_variant | Exon 2 of 2 | XP_011533351.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.564_565delGA | p.Lys188AsnfsTer21 | frameshift_variant | Exon 2 of 2 | 1 | NM_004004.6 | ENSP00000372299.4 | ||
GJB2 | ENST00000382844.2 | c.564_565delGA | p.Lys188AsnfsTer21 | frameshift_variant | Exon 1 of 1 | 6 | ENSP00000372295.1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251358Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135868
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461766Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727176
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74366
ClinVar
Submissions by phenotype
not provided Pathogenic:2
PM2_moderate, PVS1_strong -
The GJB2 c.564_565delGA; p.Lys188AsnfsTer21 variant (rs770116143) is reported in the literature in an individual with hearing loss (Azaiez 2004). This variant is also reported in ClinVar (Variation ID: 371691). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Azaiez H et al. GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum Mutat. 2004 Oct;24(4):305-11. PMID: 15365987. -
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:1
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Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
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Rare genetic deafness Pathogenic:1
The p.Lys188fs variant in GJB2 has been reported in 1 individual with hearing lo ss (Azaiez 2004). This variant has been identified in 2/10270 African chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs770116143); however, this frequency is low enough to be consistent with a r ecessive carrier frequency. This variant is predicted to cause a frameshift, whi ch alters the protein?s amino acid sequence beginning at position 188 and leads to a premature termination codon 21 amino acids downstream. In summary, this var iant is pathogenic for autosomal recessive hearing loss based on its predicted i mpact on the protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at