NM_001365536.1:c.3002A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_001365536.1(SCN9A):c.3002A>G(p.Tyr1001Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000704 in 1,561,280 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y1001Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00072 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:10B:7

Conservation

PhyloP100: 1.83

Publications

7 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: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_001365536.1

BP4

Computational evidence support a benign effect (MetaRNN=0.01835671).

BP6

Variant 2-166272748-T-C is Benign according to our data. Variant chr2-166272748-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130260.

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.3002A>G	p.Tyr1001Cys	missense	Exon 17 of 27	NP_001352465.1	Q15858-1
SCN9A	NM_002977.4		c.2969A>G	p.Tyr990Cys	missense	Exon 17 of 27	NP_002968.2	Q15858-3
SCN1A-AS1	NR_110260.1		n.870-4340T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	ENST00000642356.2	MANE Select	c.3002A>G	p.Tyr1001Cys	missense	Exon 17 of 27	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11	TSL:5	c.3002A>G	p.Tyr1001Cys	missense	Exon 17 of 27	ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5	TSL:5	c.2969A>G	p.Tyr990Cys	missense	Exon 17 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes

AF:

0.000547

AC:

AN:

151856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000634

AC:

130

AN:

205034

AF XY:

0.000590

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00513

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000266

Gnomad NFE exome

AF:

0.000856

Gnomad OTH exome

AF:

0.00127

GnomAD4 exome

AF:

0.000721

AC:

1016

AN:

1409424

Hom.:

Cov.:

AF XY:

0.000731

AC XY:

509

AN XY:

696032

show subpopulations

African (AFR)

AF:

0.000159

AC:

AN:

31364

American (AMR)

AF:

0.0000840

AC:

AN:

35728

Ashkenazi Jewish (ASJ)

AF:

0.00458

AC:

105

AN:

22912

East Asian (EAS)

AF:

0.00

AC:

AN:

39202

South Asian (SAS)

AF:

0.0000921

AC:

AN:

75998

European-Finnish (FIN)

AF:

0.000175

AC:

AN:

51356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5482

European-Non Finnish (NFE)

AF:

0.000788

AC:

858

AN:

1089384

Other (OTH)

AF:

0.000500

AC:

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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:

0.000547

AC:

AN:

151856

Hom.:

Cov.:

AF XY:

0.000553

AC XY:

AN XY:

74100

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41394

American (AMR)

AF:

0.000132

AC:

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

67992

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000928

Hom.:

Bravo

AF:

0.000620

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000276

AC:

ESP6500EA

AF:

0.00111

AC:

ExAC

AF:

0.000580

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

Primary erythromelalgia (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)

not specified (1)

Paroxysmal extreme pain disorder (1)

Self-limited epilepsy with centrotemporal spikes (1)

Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Benign

0.024

Eigen_PC

Benign

0.057

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.018

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.5

PhyloP100

1.8

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.052

Vest4

0.72

MVP

0.73

MPC

0.62

ClinPred

0.13

GERP RS

5.4

Varity_R

0.53

gMVP

0.54

Mutation Taster

=53/47

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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