rs121908908

Variant names:

• chr2-166286562-G-A
• rs121908908
• NM_001365536.1:c.1376C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166286562-G-A
• chr2-166286562-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001365536.1(SCN9A):​c.1376C>T​(p.Ser459Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,451,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45
• Publications: 9 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 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.1376C>T	p.Ser459Leu	missense	Exon 11 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.1376C>T	p.Ser459Leu	missense	Exon 11 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.1030-8003G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1376C>T	p.Ser459Leu	missense	Exon 11 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.1376C>T	p.Ser459Leu	missense	Exon 11 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.1376C>T	p.Ser459Leu	missense	Exon 11 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000255 AC: 6 AN: 235620 AF XY: 0.0000235

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000619

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1451668 Hom.: 0 Cov.: 31 AF XY: 0.00000693 AC XY: 5 AN XY: 721626

African (AFR) AF: 0.00 AC: 0 AN: 32596

American (AMR) AF: 0.0000471 AC: 2 AN: 42500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25782

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.0000477 AC: 4 AN: 83806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108712

Other (OTH) AF: 0.0000501 AC: 3 AN: 59916

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000249 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.00067
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.6	L
PhyloP100		2.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.35
Sift	Benign	0.046	D
Sift4G	Benign	0.14	T
Polyphen		0.0090	B
Vest4		0.55
MVP		0.82
MPC		0.11
ClinPred		0.67	D
GERP RS		5.9
Varity_R		0.20
gMVP		0.37
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs121908908; hg19: chr2-167143072;