rs190664764

Variant names:

• chr2-166251876-G-A
• rs190664764
• NM_001365536.1:c.3361C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001365536.1(SCN9A):​c.3361C>T​(p.Arg1121Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,612,016 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1121Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (28 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.427
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP6: Variant 2-166251876-G-A is Benign according to our data. Variant chr2-166251876-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AD,SD,AR gene

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.3361C>T	p.Arg1121Trp	missense	Exon 18 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.3328C>T	p.Arg1110Trp	missense	Exon 18 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.833G>A		non_coding_transcript_exon	Exon 7 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3361C>T	p.Arg1121Trp	missense	Exon 18 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.3361C>T	p.Arg1121Trp	missense	Exon 18 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.3328C>T	p.Arg1110Trp	missense	Exon 18 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 151836 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000484

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: 0.0342

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00350 AC: 868 AN: 247866 AF XY: 0.00349

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0315

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00351

GnomAD4 exome AF: 0.00185 AC: 2707 AN: 1460062 Hom.: 28 Cov.: 31 AF XY: 0.00181 AC XY: 1315 AN XY: 726276

African (AFR) AF: 0.0000898 AC: 3 AN: 33398

American (AMR) AF: 0.0000673 AC: 3 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86172

European-Finnish (FIN) AF: 0.0315 AC: 1678 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000841 AC: 934 AN: 1110920

Other (OTH) AF: 0.00144 AC: 87 AN: 60250

GnomAD4 genome AF: 0.00281 AC: 427 AN: 151954 Hom.: 5 Cov.: 32 AF XY: 0.00440 AC XY: 327 AN XY: 74272

African (AFR) AF: 0.0000482 AC: 2 AN: 41482

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

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

European-Finnish (FIN) AF: 0.0342 AC: 361 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000913 AC: 62 AN: 67944

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000628 Hom.: 2

Bravo AF: 0.000378

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.000854 AC: 7

ExAC AF: 0.00318 AC: 384

EpiCase AF: 0.000712

EpiControl AF: 0.000773

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	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	0.098
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0049	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.43
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.015	D
Vest4		0.29
MVP		0.71
MPC		0.42
ClinPred		0.037	T
GERP RS		3.9
Varity_R		0.19
gMVP		0.38
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs190664764; hg19: chr2-167108386; COSMIC: COSV57601840;