rs200374987

Positions:

• chr2-166281777-C-A
• chr2-166281777-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.2006G>T​(p.Arg669Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R669R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22222528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2006G>T	p.Arg669Leu	missense_variant	13/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2006G>T	p.Arg669Leu	missense_variant	13/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2006G>T	p.Arg669Leu	missense_variant	13/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1973G>T	p.Arg658Leu	missense_variant	13/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1973G>T	p.Arg658Leu	missense_variant	13/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1973G>T	p.Arg658Leu	missense_variant	13/15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jul 12, 2022

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 658 of the SCN9A protein (p.Arg658Leu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1062121). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	.;D;.;.;D;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.30	T;.;T;T;T;T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	2.0	.;M;.;.;M;M;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D;D;.;.;.;D;.
REVEL	Uncertain	0.30
Sift	Benign	0.17	T;D;.;.;.;T;.
Sift4G	Benign	0.32	T;T;.;.;.;T;.
Polyphen		0.0010	.;B;.;.;B;.;.
Vest4		0.37
MVP		0.74
MPC		0.15
ClinPred		0.45	T
GERP RS		3.9
Varity_R		0.10
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-167138287;