2-166284560-C-T

Variant names:

• chr2-166284560-C-T
• rs200398202
• NM_001365536.1:c.1867G>A

Variant summary

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

The NM_001365536.1(SCN9A):​c.1867G>A​(p.Asp623Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,840 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: 0.0000048 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.86

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1867G>A	p.Asp623Asn	missense_variant	Exon 12 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1867G>A	p.Asp623Asn	missense_variant	Exon 12 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1867G>A	p.Asp623Asn	missense_variant	Exon 12 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1867G>A	p.Asp623Asn	missense_variant	Exon 12 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1867G>A	p.Asp623Asn	missense_variant	Exon 12 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1867G>A	p.Asp623Asn	missense_variant	Exon 12 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Small fiber neuropathy Pathogenic:1

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 623 of the SCN9A protein (p.Asp623Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with small fiber neuropathy (PMID: 21698661). ClinVar contains an entry for this variant (Variation ID: 30358). 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%. Experimental studies have shown that this missense change affects SCN9A function (PMID: 21698661, 23850641). 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	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	.;D;.;.;D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.3	M;M;M;.;M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.1	D;.;.;.;.;D;.
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Benign	0.089	T;T;.;.;.;T;.
Polyphen		0.27	.;B;.;.;B;.;.
Vest4		0.84
MVP		0.80
MPC		0.54
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.60

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: rs200398202; hg19: chr2-167141070;