rs121908908

Positions:

• chr2-166286562-G-A
• chr2-166286562-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001365536.1(SCN9A):​c.1376C>T​(p.Ser459Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,451,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN1A-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1376C>T	p.Ser459Leu	missense_variant	11/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1376C>T	p.Ser459Leu	missense_variant	11/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1376C>T	p.Ser459Leu	missense_variant	11/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1376C>T	p.Ser459Leu	missense_variant	11/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1376C>T	p.Ser459Leu	missense_variant	11/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1376C>T	p.Ser459Leu	missense_variant	11/15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000255 AC: 6 AN: 235620 Hom.: 0 AF XY: 0.0000235 AC XY: 3 AN XY: 127762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000619

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000141

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1451668 Hom.: 0 Cov.: 31 AF XY: 0.00000693 AC XY: 5 AN XY: 721626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000471

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000477

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000501

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000249 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 459 of the SCN9A protein (p.Ser459Leu). This variant is present in population databases (rs121908908, gnomAD 0.01%). ClinVar contains an entry for this variant (Variation ID: 1019651). 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 SCN9A 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	.;D;.;.;D;.;.
Eigen	Benign	0.00067
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;T;T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.6	L;L;L;.;L;L;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D;.;.;.;.;D;.
REVEL	Uncertain	0.35
Sift	Benign	0.046	D;.;.;.;.;D;.
Sift4G	Benign	0.14	T;T;.;.;.;T;.
Polyphen		0.0090	.;B;.;.;B;.;.
Vest4		0.55
MVP		0.82
MPC		0.11
ClinPred		0.67	D
GERP RS		5.9
Varity_R		0.20
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908908; hg19: chr2-167143072;