rs368691761

Positions:

• chr2-166272828-G-C
• chr2-166272828-G-T

Variant summary

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

The NM_001365536.1(SCN9A):​c.2922C>G​(p.Asp974Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,364,406 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07

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 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.2922C>G	p.Asp974Glu	missense_variant	17/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2922C>G	p.Asp974Glu	missense_variant	17/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2922C>G	p.Asp974Glu	missense_variant	17/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2889C>G	p.Asp963Glu	missense_variant	17/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2889C>G	p.Asp963Glu	missense_variant	17/27			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000116 AC: 2 AN: 172670 Hom.: 0 AF XY: 0.0000220 AC XY: 2 AN XY: 90962

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1364406 Hom.: 0 Cov.: 31 AF XY: 0.00000299 AC XY: 2 AN XY: 668552

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: 0.0000298

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000868 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.;.;D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;.;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.6	.;M;.;.;M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;.;.;.;.;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;.;.;.;.;D
Sift4G	Benign	0.37	T;T;.;.;.;T
Vest4		0.70
MutPred		0.19		Gain of disorder (P = 0.1024);.;Gain of disorder (P = 0.1024);Gain of disorder (P = 0.1024);.;.;
MVP		0.83
MPC		0.34
ClinPred		0.91	D
GERP RS		3.6
Varity_R		0.82
gMVP		0.47

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: rs368691761; hg19: chr2-167129338;