NM_001365536.1:c.390G>T

Variant names:

• chr2-166306587-C-A
• rs376036522
• NM_001365536.1:c.390G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001365536.1(SCN9A):​c.390G>T​(p.Met130Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,574,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.34
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40673864).

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.390G>T	p.Met130Ile	missense	Exon 4 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.390G>T	p.Met130Ile	missense	Exon 4 of 27	NP_002968.2	Q15858-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.390G>T	p.Met130Ile	missense	Exon 4 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.390G>T	p.Met130Ile	missense	Exon 4 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.390G>T	p.Met130Ile	missense	Exon 4 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000257 AC: 5 AN: 194418 AF XY: 0.0000290

Gnomad AFR exome AF: 0.0000840

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: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 76 AN: 1422724 Hom.: 0 Cov.: 31 AF XY: 0.0000611 AC XY: 43 AN XY: 704172

African (AFR) AF: 0.00 AC: 0 AN: 32880

American (AMR) AF: 0.00 AC: 0 AN: 39382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25510

East Asian (EAS) AF: 0.00 AC: 0 AN: 38602

South Asian (SAS) AF: 0.00 AC: 0 AN: 81412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.0000698 AC: 76 AN: 1088980

Other (OTH) AF: 0.00 AC: 0 AN: 58974

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74286

African (AFR) AF: 0.0000724 AC: 3 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000895 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.0000418 AC: 5

ClinVar

ClinVar submissions

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	Benign	0.29
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.012	D
Sift4G	Benign	0.17	T
Polyphen		0.011	B
Vest4		0.27
MVP		0.84
MPC		0.14
ClinPred		0.22	T
GERP RS		6.0
Varity_R		0.52
gMVP		0.35
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: rs376036522; hg19: chr2-167163097;