rs200970256

Variant names:

• chr2-166281779-C-A
• rs200970256
• NM_001365536.1:c.2004G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166281779-C-A
• chr2-166281779-C-T

Variant summary

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

The NM_001365536.1(SCN9A):​c.2004G>T​(p.Arg668Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,478 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R668W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.114
• Publications: 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.2004G>T	p.Arg668Ser	missense	Exon 13 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.1971G>T	p.Arg657Ser	missense	Exon 13 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.1029+4532C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.2004G>T	p.Arg668Ser	missense	Exon 13 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.2004G>T	p.Arg668Ser	missense	Exon 13 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.1971G>T	p.Arg657Ser	missense	Exon 13 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 248060 AF XY: 0.0000223

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1460510 Hom.: 0 Cov.: 30 AF XY: 0.0000317 AC XY: 23 AN XY: 726488

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.0000224 AC: 1 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111310

Other (OTH) AF: 0.0000166 AC: 1 AN: 60330

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151968 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74216

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.11
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.60
Sift	Benign	0.053	T
Sift4G	Benign	0.31	T
Polyphen		0.15	B
Vest4		0.71
MVP		0.70
MPC		0.52
ClinPred		0.18	T
GERP RS		2.0
Varity_R		0.21
gMVP		0.59
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200970256; hg19: chr2-167138289; COSMIC: COSV108849551; COSMIC: COSV108849551;