2-166277030-T-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.2827A>C(p.Met943Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0108 in 1,613,876 control chromosomes in the GnomAD database, including 1,236 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. M943I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 116 hom., cov: 32)

Exomes 𝑓: 0.010 ( 1120 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 6.19

Publications

39 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=0.0031083524).

BP6

Variant 2-166277030-T-G is Benign according to our data. Variant chr2-166277030-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0929 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.2827A>C	p.Met943Leu	missense	Exon 16 of 27	NP_001352465.1	Q15858-1
SCN9A	NM_002977.4		c.2794A>C	p.Met932Leu	missense	Exon 16 of 27	NP_002968.2	Q15858-3
SCN1A-AS1	NR_110260.1		n.870-58T>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	ENST00000642356.2	MANE Select	c.2827A>C	p.Met943Leu	missense	Exon 16 of 27	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11	TSL:5	c.2827A>C	p.Met943Leu	missense	Exon 16 of 27	ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5	TSL:5	c.2794A>C	p.Met932Leu	missense	Exon 16 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes

AF:

0.0147

AC:

2230

AN:

151982

Hom.:

115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0968

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0579

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00338

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.0368

AC:

9252

AN:

251290

AF XY:

0.0294

show subpopulations

Gnomad AFR exome

AF:

0.00301

Gnomad AMR exome

AF:

0.211

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.0595

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.0246

GnomAD4 exome

AF:

0.0103

AC:

15113

AN:

1461776

Hom.:

1120

Cov.:

AF XY:

0.00950

AC XY:

6907

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00191

AC:

AN:

33466

American (AMR)

AF:

0.192

AC:

8606

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

26132

East Asian (EAS)

AF:

0.0508

AC:

2015

AN:

39700

South Asian (SAS)

AF:

0.0116

AC:

999

AN:

86254

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00242

AC:

2692

AN:

1111942

Other (OTH)

AF:

0.0109

AC:

661

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

902

1803

2705

3606

4508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

242

484

726

968

1210

<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:

0.0147

AC:

2239

AN:

152100

Hom.:

116

Cov.:

AF XY:

0.0163

AC XY:

1214

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00275

AC:

114

AN:

41502

American (AMR)

AF:

0.0970

AC:

1481

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.0581

AC:

300

AN:

5166

South Asian (SAS)

AF:

0.0145

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00338

AC:

230

AN:

67970

Other (OTH)

AF:

0.0151

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

101

202

302

403

504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00883

Hom.:

117

Bravo

AF:

0.0236

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.0295

AC:

3581

Asia WGS

AF:

0.0310

AC:

106

AN:

3478

EpiCase

AF:

0.00333

EpiControl

AF:

0.00225

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Channelopathy-associated congenital insensitivity to pain, autosomal recessive (2)

Autism spectrum disorder (1)

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

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

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.23

Eigen_PC

Benign

0.052

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.52

MutationAssessor

Benign

-0.10

PhyloP100

6.2

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.57

Sift

Benign

0.31

Sift4G

Benign

1.0

Vest4

0.70

MutPred

0.65

Gain of helix (P = 0.062)

MPC

0.17

ClinPred

0.015

GERP RS

5.7

Varity_R

0.54

gMVP

0.73

Mutation Taster

=25/75

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