rs781223783

Positions:

• chr2-166272538-A-C
• chr2-166272538-A-G
• chr2-166272538-A-T

Variant summary

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

The NM_001365536.1(SCN9A):​c.3212T>G​(p.Met1071Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.60

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/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3212T>G	p.Met1071Arg	missense_variant	17/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.870-4550A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3212T>G	p.Met1071Arg	missense_variant	17/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1548-4550A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Feb 07, 2018

This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with arginine at codon 1060 of the SCN9A protein (p.Met1060Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. This variant has not been reported in the literature in individuals with SCN9A-related disease. 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 (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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.47	.;T;.;.;T;.
Eigen	Benign	-0.056
Eigen_PC	Benign	0.062
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.65	T;.;T;T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.4	.;L;.;.;L;L
MutationTaster	Benign	0.81	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D;.;.;.;.;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;.;.;.;.;D
Sift4G	Benign	0.61	T;T;.;.;.;T
Vest4		0.69
MutPred		0.42		Loss of methylation at K1057 (P = 0.0848);.;Loss of methylation at K1057 (P = 0.0848);Loss of methylation at K1057 (P = 0.0848);.;.;
MVP		0.75
MPC		0.22
ClinPred		0.91	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs781223783; hg19: chr2-167129048;