rs200174262
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001365536.1(SCN9A):c.2005C>T(p.Arg669Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000893 in 1,612,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R669H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001365536.1 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 |
---|---|---|---|---|---|---|---|
SCN9A | NM_001365536.1 | c.2005C>T | p.Arg669Cys | missense_variant | 13/27 | ENST00000642356.2 | |
SCN1A-AS1 | NR_110260.1 | n.1029+4531G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.2005C>T | p.Arg669Cys | missense_variant | 13/27 | NM_001365536.1 | P1 | ||
SCN1A-AS1 | ENST00000651574.1 | n.1707+4531G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000336 AC: 51AN: 151924Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000117 AC: 29AN: 247644Hom.: 0 AF XY: 0.0000968 AC XY: 13AN XY: 134336
GnomAD4 exome AF: 0.0000637 AC: 93AN: 1460354Hom.: 0 Cov.: 30 AF XY: 0.0000496 AC XY: 36AN XY: 726410
GnomAD4 genome ? AF: 0.000335 AC: 51AN: 152042Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24AN XY: 74316
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 08, 2022 | The p.R658C variant (also known as c.1972C>T), located in coding exon 12 of the SCN9A gene, results from a C to T substitution at nucleotide position 1972. The arginine at codon 658 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species, and cysteine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of primary erythermalgia/small fiber neuropathy and paroxysmal extreme pain disorder (PEPD); however, its contribution to the development of congenital insensitivity to pain (CIP) and hereditary sensory autonomic neuropathy type II (HSAN2D) is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at