dbSNP rs73969684: SCN9A:p.Arg185His (chr2-166305834-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365536.1(SCN9A):c.554G>A(p.Arg185His) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,613,182 control chromosomes in the GnomAD database, including 15 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. R185C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0054 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 9 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2B:13

Conservation

PhyloP100: 6.16

Publications

28 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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.01727277).

BP6

Variant 2-166305834-C-T is Benign according to our data. Variant chr2-166305834-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00541 (821/151808) while in subpopulation AFR AF = 0.0138 (572/41408). AF 95% confidence interval is 0.0129. There are 6 homozygotes in GnomAd4. There are 386 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 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.554G>A	p.Arg185His	missense	Exon 5 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.554G>A	p.Arg185His	missense	Exon 5 of 27	NP_002968.2	Q15858-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	ENST00000642356.2	MANE Select	c.554G>A	p.Arg185His	missense	Exon 5 of 27	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11	TSL:5	c.554G>A	p.Arg185His	missense	Exon 5 of 27	ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5	TSL:5	c.554G>A	p.Arg185His	missense	Exon 5 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes

AF:

0.00541

AC:

820

AN:

151690

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00171

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00559

Gnomad SAS

AF:

0.000832

Gnomad FIN

AF:

0.00218

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00221

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00280

AC:

698

AN:

249044

AF XY:

0.00261

show subpopulations

Gnomad AFR exome

AF:

0.0137

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00417

Gnomad FIN exome

AF:

0.00288

Gnomad NFE exome

AF:

0.00253

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00209

AC:

3049

AN:

1461374

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

1450

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.0130

AC:

434

AN:

33468

American (AMR)

AF:

0.00105

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00219

AC:

AN:

39686

South Asian (SAS)

AF:

0.000742

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00272

AC:

145

AN:

53400

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00185

AC:

2061

AN:

1111608

Other (OTH)

AF:

0.00345

AC:

208

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

160

320

481

641

801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.00541

AC:

821

AN:

151808

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

386

AN XY:

74208

show subpopulations

African (AFR)

AF:

0.0138

AC:

572

AN:

41408

American (AMR)

AF:

0.00171

AC:

AN:

15194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00560

AC:

AN:

5176

South Asian (SAS)

AF:

0.000833

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00218

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00221

AC:

150

AN:

67898

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00290

Hom.:

Bravo

AF:

0.00541

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.0135

AC:

ESP6500EA

AF:

0.00219

AC:

ExAC

AF:

0.00330

AC:

399

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00130

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

Paroxysmal extreme pain disorder (2)

Small fiber neuropathy (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)

Primary erythromelalgia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.017

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

3.8

PhyloP100

6.2

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.92

MVP

0.92

MPC

0.62

ClinPred

0.11

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.91

Mutation Taster

=22/78

disease causing

(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