rs781223783

Variant names:

• chr2-166272538-A-C
• rs781223783
• NM_001365536.1:c.3212T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1071T) has been classified 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
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365536.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.3212T>G	p.Met1071Arg	missense	Exon 17 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.3179T>G	p.Met1060Arg	missense	Exon 17 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.870-4550A>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3212T>G	p.Met1071Arg	missense	Exon 17 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.3212T>G	p.Met1071Arg	missense	Exon 17 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.3179T>G	p.Met1060Arg	missense	Exon 17 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

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

Feb 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. This variant has not been reported in the literature in individuals with SCN9A-related disease. This variant is not present in population databases (ExAC no frequency).

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.056
Eigen_PC	Benign	0.062
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.6
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.61	T
Vest4		0.69
MutPred		0.42		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
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs781223783; hg19: chr2-167129048;