rs28938175
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_004086.3(COCH):c.151C>T(p.Pro51Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,888 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. P51P) has been classified as Likely benign.
Frequency
Consequence
NM_004086.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COCH | NM_004086.3 | c.151C>T | p.Pro51Ser | missense_variant | 4/12 | ENST00000396618.9 | |
LOC100506071 | NR_038356.1 | n.1618-1088G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COCH | ENST00000396618.9 | c.151C>T | p.Pro51Ser | missense_variant | 4/12 | 1 | NM_004086.3 | P1 | |
ENST00000555108.1 | n.1618-1088G>A | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251472Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135916
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461888Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Nonsyndromic genetic hearing loss Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Sep 19, 2018 | The c.151C>T (p.Pro51Ser) variant in COCH has been reported to segregate with late onset progressive hearing loss and vestibular dysfunction in > 25 family members (PP1_S; PMID: 9931344, 11332404). The variant meets PM2 and has been observed in at least 15 affected probands (PS4, PMID: 28733840, 16151338, 11332404). The allele frequency of the p.Pro51Ser variant is 0.001% (1/111716) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (PM2). Computational prediction tools and conservation analysis suggest that the p.Pro51Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_S, PS4, PM2, PP3. - |
Hearing impairment Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PS1_Strong, PM2_Moderate, PP3_Supporting - |
Autosomal dominant nonsyndromic hearing loss 9 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2009 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 14, 2011 | The Pro51Ser variant in COCH has segregated in many Dutch families with late ons et autosomal dominant progressive sensorineural hearing loss with vestibular def ects (Bischoff 2005, de Kok 1999, Fransen 2001). It has been suggested that this variant is likely a found mutation in the Dutch population. In summary, this va riant meets our criteria to be classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at