chr2-166242648-A-G

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.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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.38

Publications

139 publications found

Variant links:

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

ACMG classification

Classification was made for transcript

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

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

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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.869

AC XY:

598906

AN XY:

688988

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

7105

14209

21314

28418

35523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20862

41724

62586

83448

104310

<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:

0.878

AC:

133538

AN:

152026

Hom.:

58696

Cov.:

AF XY:

0.877

AC XY:

65188

AN XY:

74304

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

819

1637

2456

3274

4093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

900

1800

2700

3600

4500

<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:

0.871

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

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.17

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.035

MetaRNN

Benign

0.0000023

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-3.3

PhyloP100

1.4

PrimateAI

Benign

0.29

PROVEAN

Benign

5.2

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.044

MutPred

0.54

Gain of disorder (P = 0.0309)

MPC

0.21

ClinPred

0.0020

GERP RS

3.8

Varity_R

0.098

gMVP

0.28

Mutation Taster

=100/0

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

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