chr5-149040658-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_024577.4(SH3TC2):c.751C>T(p.Pro251Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,614,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024577.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SH3TC2 | NM_024577.4 | c.751C>T | p.Pro251Ser | missense_variant | Exon 7 of 17 | ENST00000515425.6 | NP_078853.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000256 AC: 39AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000215 AC: 54AN: 251402Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135868
GnomAD4 exome AF: 0.000534 AC: 780AN: 1461838Hom.: 1 Cov.: 31 AF XY: 0.000531 AC XY: 386AN XY: 727228
GnomAD4 genome AF: 0.000256 AC: 39AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17AN XY: 74326
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
BP4 -
SH3TC2: BP4 -
A variant of uncertain significance has been identified in the SH3TC2 gene. The P251S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P251S variant is observed in 17/66,674 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P251S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
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The SH3TC2 c.751C>T; p.Pro251Ser variant (rs144963732), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.04% (identified on 48 out of 126,674 chromosomes). The proline at position 251 is highly conserved, considering 8 species, and computational analyses of the effects of the p.Pro251Ser variant on protein structure and function make conflicting predictions (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Based on all available evidence, the clinical significance of the p.Pro251Ser variant cannot be determined with certainty. -
Charcot-Marie-Tooth disease Uncertain:1
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Charcot-Marie-Tooth disease type 4C Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Inborn genetic diseases Uncertain:1
The p.P251S variant (also known as c.751C>T), located in coding exon 7 of the SH3TC2 gene, results from a C to T substitution at nucleotide position 751. The proline at codon 251 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Susceptibility to mononeuropathy of the median nerve, mild Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Charcot-Marie-Tooth disease type 4 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at