chr2-166272746-C-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1
The NM_001365536.1(SCN9A):c.3004G>T(p.Val1002Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00941 in 1,563,390 control chromosomes in the GnomAD database, including 899 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001365536.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN9A | NM_001365536.1 | c.3004G>T | p.Val1002Leu | missense_variant | Exon 17 of 27 | ENST00000642356.2 | NP_001352465.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.3004G>T | p.Val1002Leu | missense_variant | Exon 17 of 27 | NM_001365536.1 | ENSP00000495601.1 | |||
SCN9A | ENST00000303354.11 | c.3004G>T | p.Val1002Leu | missense_variant | Exon 17 of 27 | 5 | ENSP00000304748.7 | |||
SCN9A | ENST00000409672.5 | c.2971G>T | p.Val991Leu | missense_variant | Exon 17 of 27 | 5 | ENSP00000386306.1 | |||
SCN9A | ENST00000645907.1 | c.2971G>T | p.Val991Leu | missense_variant | Exon 17 of 27 | ENSP00000495983.1 |
Frequencies
GnomAD3 genomes AF: 0.0144 AC: 2191AN: 151674Hom.: 108 Cov.: 31
GnomAD3 exomes AF: 0.0332 AC: 6843AN: 206416Hom.: 629 AF XY: 0.0269 AC XY: 2990AN XY: 111038
GnomAD4 exome AF: 0.00886 AC: 12507AN: 1411598Hom.: 790 Cov.: 31 AF XY: 0.00835 AC XY: 5824AN XY: 697362
GnomAD4 genome AF: 0.0145 AC: 2200AN: 151792Hom.: 109 Cov.: 31 AF XY: 0.0159 AC XY: 1181AN XY: 74126
ClinVar
Submissions by phenotype
not specified Benign:5
This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 21. Only high quality variants are reported. -
Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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not provided Benign:4
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This variant is associated with the following publications: (PMID: 25585270, 27956748, 26284228, 27535533, 21698661) -
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Primary erythromelalgia Uncertain:1Benign:2
The heterozygous p.Val991Leu variant in SCN9A has been identified in an individual suspected to have small fibre neuropathy (PMID: 21698661). In vitro functional studies provide some evidence that the p.Pro124Ser variant will not impact protein function (PMID: 21698661). However, these types of assays may not accurately represent biological function. This variant is classified as benign for autosomal dominant small fibre neuropathy because it has been identified in >20% of Latino chromosomes, including 340 homozygotes, by ExAC (http://gnomad.broadinstitute.org/). -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
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Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1
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Small fiber neuropathy Benign:1
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Paroxysmal extreme pain disorder Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at