rs140736502
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_033056.4(PCDH15):c.949T>A(p.Ser317Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,680 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S317S) has been classified as Likely benign.
Frequency
Consequence
NM_033056.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.949T>A | p.Ser317Thr | missense_variant | 9/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.949T>A | p.Ser317Thr | missense_variant | 9/38 | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.949T>A | p.Ser317Thr | missense_variant | 9/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.949T>A | p.Ser317Thr | missense_variant | 9/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.000802 AC: 122AN: 152114Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000195 AC: 49AN: 251406Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135866
GnomAD4 exome AF: 0.0000623 AC: 91AN: 1461448Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 727036
GnomAD4 genome ? AF: 0.000795 AC: 121AN: 152232Hom.: 1 Cov.: 33 AF XY: 0.000793 AC XY: 59AN XY: 74434
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2018 | The S317T variant in the PCDH15 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S317T variant is observed in 60/277126 (0.022%) alleles in large population cohorts, with no homozygotes observed (Lek et al., 2016). The S317T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret S317T as a variant of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 09, 2015 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 11, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 03, 2019 | The p.Ser317Thr variant in PCDH15 has been previously reported by our laboratory in 1 individuals with hearing loss, and was also identified in 0.24% (60/24968) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This varia nt has also been reported in ClinVar (Variation iD 96235). Computational predict ion tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser317 Thr variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting. - |
Autosomal recessive nonsyndromic hearing loss 23 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Oct 08, 2019 | Two variants in this gene (PCDH15) were found to be in cis (both were inherited form the mother) in a young male with postlingual bilateral severe hearing loss - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at