1-44828607-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_003738.5(PTCH2):c.1489C>T(p.Arg497Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,368 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R497H) has been classified as Uncertain significance.
Frequency
Consequence
NM_003738.5 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 |
---|---|---|---|---|---|---|---|
PTCH2 | NM_003738.5 | c.1489C>T | p.Arg497Cys | missense_variant | 12/22 | ENST00000372192.4 | |
PTCH2 | NM_001166292.2 | c.1489C>T | p.Arg497Cys | missense_variant | 12/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTCH2 | ENST00000372192.4 | c.1489C>T | p.Arg497Cys | missense_variant | 12/22 | 1 | NM_003738.5 | P2 | |
PTCH2 | ENST00000447098.6 | c.1489C>T | p.Arg497Cys | missense_variant | 12/23 | 1 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248146Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134480
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461030Hom.: 0 Cov.: 35 AF XY: 0.0000179 AC XY: 13AN XY: 726758
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152338Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74500
ClinVar
Submissions by phenotype
Gorlin syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 15, 2017 | This sequence change replaces arginine with cysteine at codon 497 of the PTCH2 protein (p.Arg497Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200815526, ExAC 0.007%) but has not been reported in the literature in individuals with a PTCH2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at