Genetic Variant NM_001365536.1:c.3004G>T (chr2-166272746-C-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

The NM_001365536.1(SCN9A):c.3004G>T(p.Val1002Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00941 in 1,563,390 control chromosomes in the GnomAD database, including 899 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1002M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 109 hom., cov: 31)

Exomes 𝑓: 0.0089 ( 790 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: -0.491

Publications

33 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 -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_001365536.1

BP4

Computational evidence support a benign effect (MetaRNN=0.0019373894).

BP6

Variant 2-166272746-C-A is Benign according to our data. Variant chr2-166272746-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94090.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0919 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.3004G>T	p.Val1002Leu	missense	Exon 17 of 27	NP_001352465.1	Q15858-1
SCN9A	NM_002977.4		c.2971G>T	p.Val991Leu	missense	Exon 17 of 27	NP_002968.2	Q15858-3
SCN1A-AS1	NR_110260.1		n.870-4342C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	ENST00000642356.2	MANE Select	c.3004G>T	p.Val1002Leu	missense	Exon 17 of 27	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11	TSL:5	c.3004G>T	p.Val1002Leu	missense	Exon 17 of 27	ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5	TSL:5	c.2971G>T	p.Val991Leu	missense	Exon 17 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2191

AN:

151674

Hom.:

108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00273

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0958

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0568

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.000285

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00337

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.0332

AC:

6843

AN:

206416

AF XY:

0.0269

show subpopulations

Gnomad AFR exome

AF:

0.00304

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.0590

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.00886

AC:

12507

AN:

1411598

Hom.:

790

Cov.:

AF XY:

0.00835

AC XY:

5824

AN XY:

697362

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

31434

American (AMR)

AF:

0.175

AC:

6313

AN:

36026

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

23052

East Asian (EAS)

AF:

0.0504

AC:

1976

AN:

39202

South Asian (SAS)

AF:

0.0115

AC:

877

AN:

76470

European-Finnish (FIN)

AF:

0.000156

AC:

AN:

51442

Middle Eastern (MID)

AF:

0.00310

AC:

AN:

5488

European-Non Finnish (NFE)

AF:

0.00239

AC:

2609

AN:

1090366

Other (OTH)

AF:

0.0104

AC:

605

AN:

58118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

578

1155

1733

2310

2888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

224

448

672

896

1120

<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:

0.0145

AC:

2200

AN:

151792

Hom.:

109

Cov.:

AF XY:

0.0159

AC XY:

1181

AN XY:

74126

show subpopulations

African (AFR)

AF:

0.00273

AC:

113

AN:

41464

American (AMR)

AF:

0.0960

AC:

1455

AN:

15160

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.0569

AC:

290

AN:

5098

South Asian (SAS)

AF:

0.0145

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000285

AC:

AN:

10518

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00337

AC:

229

AN:

67956

Other (OTH)

AF:

0.0147

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

197

295

394

492

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:

0.0101

Hom.:

143

Bravo

AF:

0.0235

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00221

AC:

ESP6500EA

AF:

0.00418

AC:

ExAC

AF:

0.0290

AC:

3502

Asia WGS

AF:

0.0310

AC:

106

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Primary erythromelalgia (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)

Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.30

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.4

PhyloP100

-0.49

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.9

REVEL

Benign

0.17

Sift

Benign

0.10

Sift4G

Benign

0.31

Vest4

0.49

MutPred

0.71

Loss of helix (P = 0.1299)

MPC

0.12

ClinPred

0.0014

GERP RS

-0.95

Varity_R

0.19

gMVP

0.50

Mutation Taster

=98/2

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