rs774510851

Positions:

• chr2-166284526-C-A
• chr2-166284526-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365536.1(SCN9A):​c.1901G>T​(p.Arg634Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. R634H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.59

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:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20850518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1901G>T	p.Arg634Leu	missense_variant	12/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1901G>T	p.Arg634Leu	missense_variant	12/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1901G>T	p.Arg634Leu	missense_variant	12/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1901G>T	p.Arg634Leu	missense_variant	12/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1901G>T	p.Arg634Leu	missense_variant	12/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1901G>T	p.Arg634Leu	missense_variant	12/15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Dec 07, 2023

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 634 of the SCN9A protein (p.Arg634Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. ClinVar contains an entry for this variant (Variation ID: 471090). 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 with a negative predictive value of 95%. 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. -

SCN9A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2023

The SCN9A c.1901G>T variant is predicted to result in the amino acid substitution p.Arg634Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T;.;.;T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.50	T;.;T;T;T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.0	N;N;N;.;N;N;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.82	N;.;.;.;.;N;.
REVEL	Benign	0.22
Sift	Uncertain	0.017	D;.;.;.;.;D;.
Sift4G	Benign	0.31	T;T;.;.;.;T;.
Polyphen		0.0	.;B;.;.;B;.;.
Vest4		0.37
MVP		0.66
MPC		0.14
ClinPred		0.26	T
GERP RS		3.9
Varity_R		0.092
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774510851; hg19: chr2-167141036;