rs775185585
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_006514.4(SCN10A):c.3691A>T(p.Ile1231Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. I1231T) has been classified as Likely benign.
Frequency
Consequence
NM_006514.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.3691A>T | p.Ile1231Leu | missense_variant | 22/28 | ENST00000449082.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.3691A>T | p.Ile1231Leu | missense_variant | 22/28 | 1 | NM_006514.4 | P4 | |
SCN10A | ENST00000655275.1 | c.3715A>T | p.Ile1239Leu | missense_variant | 22/28 | ||||
SCN10A | ENST00000643924.1 | c.3688A>T | p.Ile1230Leu | missense_variant | 21/27 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251398Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135870
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461860Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 727230
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74376
ClinVar
Submissions by phenotype
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | 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. 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 not expected to disrupt SCN10A protein function. ClinVar contains an entry for this variant (Variation ID: 581393). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. This variant is present in population databases (rs775185585, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1231 of the SCN10A protein (p.Ile1231Leu). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2020 | The p.I1231L variant (also known as c.3691A>T), located in coding exon 21 of the SCN10A gene, results from an A to T substitution at nucleotide position 3691. The isoleucine at codon 1231 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at