2-166286469-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001365536.1(SCN9A):c.1469G>A(p.Ser490Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,832 control chromosomes in the GnomAD database, including 758 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S490T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.041 ( 389 hom., cov: 31)

Exomes 𝑓: 0.0078 ( 369 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.386

Publications

19 publications found

Variant links:

COSMIC-nc: COSV104409075

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]

SCN9A links:

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

SCN1A-AS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001365536.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016465783).

BP6

Variant 2-166286469-C-T is Benign according to our data. Variant chr2-166286469-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	NM_001365536.1	MANE Select	c.1469G>A	p.Ser490Asn	missense	Exon 11 of 27	NP_001352465.1	Q15858-1
SCN9A	NM_002977.4		c.1469G>A	p.Ser490Asn	missense	Exon 11 of 27	NP_002968.2	Q15858-3
SCN1A-AS1	NR_110260.1		n.1030-8096C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	ENST00000642356.2	MANE Select	c.1469G>A	p.Ser490Asn	missense	Exon 11 of 27	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11	TSL:5	c.1469G>A	p.Ser490Asn	missense	Exon 11 of 27	ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5	TSL:5	c.1469G>A	p.Ser490Asn	missense	Exon 11 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes

AF:

0.0412

AC:

6264

AN:

152116

Hom.:

389

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0200

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0160

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00353

Gnomad OTH

AF:

0.0349

GnomAD2 exomes

AF:

0.0152

AC:

3780

AN:

249102

AF XY:

0.0140

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.00849

Gnomad ASJ exome

AF:

0.0358

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.00368

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.00775

AC:

11334

AN:

1461598

Hom.:

369

Cov.:

AF XY:

0.00789

AC XY:

5734

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.136

AC:

4536

AN:

33464

American (AMR)

AF:

0.0102

AC:

456

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

965

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0173

AC:

1492

AN:

86224

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.0298

AC:

172

AN:

5768

European-Non Finnish (NFE)

AF:

0.00245

AC:

2728

AN:

1111824

Other (OTH)

AF:

0.0162

AC:

975

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

535

1070

1606

2141

2676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

212

424

636

848

1060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0413

AC:

6287

AN:

152234

Hom.:

389

Cov.:

AF XY:

0.0398

AC XY:

2964

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.132

AC:

5478

AN:

41526

American (AMR)

AF:

0.0201

AC:

307

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.0164

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00353

AC:

240

AN:

68018

Other (OTH)

AF:

0.0346

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

278

556

833

1111

1389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0180

Hom.:

266

Bravo

AF:

0.0455

Asia WGS

AF:

0.0130

AC:

AN:

3476

EpiCase

AF:

0.00540

EpiControl

AF:

0.00682

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (3)

Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)

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

Paroxysmal extreme pain disorder (1)

Primary erythromelalgia (1)

Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.23

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.042

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.69

PhyloP100

0.39

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.48

REVEL

Benign

0.23

Sift

Benign

0.24

Sift4G

Benign

0.41

Varity_R

0.053

gMVP

0.27

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over