rs202153871

Variant names:

• chr2-166272712-G-A
• rs202153871
• NM_001365536.1:c.3038C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166272712-G-A
• chr2-166272712-G-C
• chr2-166272712-G-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.3038C>T​(p.Ala1013Val) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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=0.15097645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3038C>T	p.Ala1013Val	missense_variant	Exon 17 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3038C>T	p.Ala1013Val	missense_variant	Exon 17 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.3038C>T	p.Ala1013Val	missense_variant	Exon 17 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.3005C>T	p.Ala1002Val	missense_variant	Exon 17 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.3005C>T	p.Ala1002Val	missense_variant	Exon 17 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Mar 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces alanine with valine at codon 1002 of the SCN9A protein (p.Ala1002Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN9A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.21	.;T;.;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.84	T;.;T;D;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.5	.;L;.;.;L;L
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.4	N;.;.;.;.;N
REVEL	Benign	0.26
Sift	Benign	0.14	T;.;.;.;.;T
Sift4G	Benign	0.42	T;T;.;.;.;T
Vest4		0.20
MutPred		0.53		Gain of methylation at K1001 (P = 0.0397);.;Gain of methylation at K1001 (P = 0.0397);Gain of methylation at K1001 (P = 0.0397);.;.;
MVP		0.57
MPC		0.12
ClinPred		0.17	T
GERP RS		4.5
Varity_R		0.11
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202153871; hg19: chr2-167129222;