rs372078622
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2
The NM_001349253.2(SCN11A):c.2288G>A(p.Arg763His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,614,060 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R763C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001349253.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN11A | NM_001349253.2 | c.2288G>A | p.Arg763His | missense_variant | 18/30 | ENST00000302328.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN11A | ENST00000302328.9 | c.2288G>A | p.Arg763His | missense_variant | 18/30 | 5 | NM_001349253.2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152066Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251320Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135824
GnomAD4 exome AF: 0.000103 AC: 150AN: 1461876Hom.: 0 Cov.: 34 AF XY: 0.000106 AC XY: 77AN XY: 727244
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152184Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74388
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN11A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 567053). This variant has not been reported in the literature in individuals affected with SCN11A-related conditions. This variant is present in population databases (rs372078622, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 763 of the SCN11A protein (p.Arg763His). - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 30, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at