rs763972874

Positions:

• chr2-166199427-A-C

Variant summary

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

The NM_001365536.1(SCN9A):​c.5212T>G​(p.Phe1738Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.29

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.5212T>G	p.Phe1738Val	missense_variant	27/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.5212T>G	p.Phe1738Val	missense_variant	27/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.5212T>G	p.Phe1738Val	missense_variant	27/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.5179T>G	p.Phe1727Val	missense_variant	27/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.5179T>G	p.Phe1727Val	missense_variant	27/27			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2019

The p.F1727V variant (also known as c.5179T>G), located in coding exon 26 of the SCN9A gene, results from a T to G substitution at nucleotide position 5179. The phenylalanine at codon 1727 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Oct 19, 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 SCN9A protein function. ClinVar contains an entry for this variant (Variation ID: 538462). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. This variant is present in population databases (rs763972874, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1727 of the SCN9A protein (p.Phe1727Val). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

SCN9A: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.72	.;D;.;.;D;.
Eigen	Benign	-0.092
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T;.;T;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	0.045	.;N;.;.;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.2	D;.;.;.;.;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.016	D;.;.;.;.;D
Sift4G	Benign	1.0	T;T;.;.;.;T
Vest4		0.68
MutPred		0.43		Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);.;.;.;
MVP		0.86
MPC		0.47
ClinPred		0.39	T
GERP RS		5.9
Varity_R		0.53
gMVP		0.80

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: rs763972874; hg19: chr2-167055937;