rs180922748

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001365536.1(SCN9A):c.3832C>G(p.Leu1278Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,576,608 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1278L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 8 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:12

Conservation

PhyloP100: 2.27

Publications

19 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031454235).

BP6

Variant 2-166233432-G-C is Benign according to our data. Variant chr2-166233432-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195592.

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR,SD 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	NM_001365536.1	MANE Select	c.3832C>G	p.Leu1278Val	missense	Exon 21 of 27	NP_001352465.1	Q15858-1
SCN9A	NM_002977.4		c.3799C>G	p.Leu1267Val	missense	Exon 21 of 27	NP_002968.2	Q15858-3
SCN1A-AS1	NR_110260.1		n.612-14763G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	ENST00000642356.2	MANE Select	c.3832C>G	p.Leu1278Val	missense	Exon 21 of 27	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11	TSL:5	c.3832C>G	p.Leu1278Val	missense	Exon 21 of 27	ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5	TSL:5	c.3799C>G	p.Leu1267Val	missense	Exon 21 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

260

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00289

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00122

AC:

261

AN:

214484

AF XY:

0.00125

show subpopulations

Gnomad AFR exome

AF:

0.000451

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000427

Gnomad NFE exome

AF:

0.00207

Gnomad OTH exome

AF:

0.000795

GnomAD4 exome

AF:

0.00214

AC:

3052

AN:

1424522

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

1456

AN XY:

707200

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

31070

American (AMR)

AF:

0.00133

AC:

AN:

36036

Ashkenazi Jewish (ASJ)

AF:

0.0000791

AC:

AN:

25284

East Asian (EAS)

AF:

0.00

AC:

AN:

37696

South Asian (SAS)

AF:

0.0000130

AC:

AN:

77168

European-Finnish (FIN)

AF:

0.000584

AC:

AN:

53096

Middle Eastern (MID)

AF:

0.00106

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00257

AC:

2830

AN:

1099474

Other (OTH)

AF:

0.00217

AC:

128

AN:

59016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

133

265

398

530

663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00171

AC:

260

AN:

152086

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41510

American (AMR)

AF:

0.00268

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000944

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00289

AC:

196

AN:

67926

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00224

Hom.:

Bravo

AF:

0.00184

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000529

AC:

ESP6500EA

AF:

0.00229

AC:

ExAC

AF:

0.00129

AC:

156

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

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)

Inborn genetic diseases (1)

Inherited Erythromelalgia (1)

Paroxysmal extreme pain disorder (1)

Primary erythromelalgia (1)

Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.031

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.4

PhyloP100

2.3

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

Sift4G

Benign

0.077

Vest4

0.39

MVP

0.87

MPC

0.46

ClinPred

0.15

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.66

gMVP

0.42

Mutation Taster

=17/83

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