NM_001365536.1:c.3481T>C

Variant names:

• chr2-166242648-A-G
• rs6746030
• NM_001365536.1:c.3481T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.3481T>C​(p.Trp1161Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,548,672 control chromosomes in the GnomAD database, including 587,761 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1161Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.88 (58696 hom., cov: 30)
  • Exomes 𝑓: 0.87 (529065 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.38
• Publications: 139 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3442258E-6).
• BP6: Variant 2-166242648-A-G is Benign according to our data. Variant chr2-166242648-A-G is described in ClinVar as Benign. ClinVar VariationId is 440255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

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.3481T>C	p.Trp1161Arg	missense	Exon 19 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.3448T>C	p.Trp1150Arg	missense	Exon 19 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.612-5547A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3481T>C	p.Trp1161Arg	missense	Exon 19 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.3481T>C	p.Trp1161Arg	missense	Exon 19 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.3448T>C	p.Trp1150Arg	missense	Exon 19 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133444 AN: 151908 Hom.: 58658 Cov.: 30

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.882

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.951

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.871

GnomAD2 exomes AF: 0.880 AC: 138994 AN: 158010 AF XY: 0.878

Gnomad AFR exome AF: 0.892

Gnomad AMR exome AF: 0.902

Gnomad ASJ exome AF: 0.912

Gnomad EAS exome AF: 0.956

Gnomad FIN exome AF: 0.893

Gnomad NFE exome AF: 0.862

Gnomad OTH exome AF: 0.875

GnomAD4 exome AF: 0.870 AC: 1215240 AN: 1396646 Hom.: 529065 Cov.: 34 AF XY: 0.869 AC XY: 598906 AN XY: 688988

African (AFR) AF: 0.893 AC: 28155 AN: 31524

American (AMR) AF: 0.897 AC: 32036 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 22870 AN: 25126

East Asian (EAS) AF: 0.950 AC: 33972 AN: 35750

South Asian (SAS) AF: 0.842 AC: 66511 AN: 79000

European-Finnish (FIN) AF: 0.894 AC: 44076 AN: 49276

Middle Eastern (MID) AF: 0.871 AC: 4952 AN: 5686

European-Non Finnish (NFE) AF: 0.866 AC: 931860 AN: 1076662

Other (OTH) AF: 0.877 AC: 50808 AN: 57924

GnomAD4 genome AF: 0.878 AC: 133538 AN: 152026 Hom.: 58696 Cov.: 30 AF XY: 0.877 AC XY: 65188 AN XY: 74304

African (AFR) AF: 0.893 AC: 37041 AN: 41472

American (AMR) AF: 0.882 AC: 13429 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 3170 AN: 3470

East Asian (EAS) AF: 0.951 AC: 4910 AN: 5164

South Asian (SAS) AF: 0.833 AC: 4015 AN: 4818

European-Finnish (FIN) AF: 0.887 AC: 9383 AN: 10580

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.864 AC: 58699 AN: 67974

Other (OTH) AF: 0.870 AC: 1840 AN: 2114

Alfa AF: 0.871 Hom.: 205981

Bravo AF: 0.882

TwinsUK AF: 0.873 AC: 3238

ALSPAC AF: 0.866 AC: 3338

ESP6500AA AF: 0.891 AC: 3274

ESP6500EA AF: 0.871 AC: 7029

ExAC AF: 0.852 AC: 64740

Asia WGS AF: 0.884 AC: 3076 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.035	T
MetaRNN	Benign	0.0000023	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.3	N
PhyloP100		1.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	5.2	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.044
MutPred		0.54		Gain of disorder (P = 0.0309)
MPC		0.21
ClinPred		0.0020	T
GERP RS		3.8
Varity_R		0.098
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs6746030; hg19: chr2-167099158; COSMIC: COSV57623295;