NM_001365536.1:c.5949C>G

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.5949C>G(p.Ser1983Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000565 in 1,593,706 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. S1983I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 2 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.21

Publications

1 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=0.025282294).

BP6

Variant 2-166198690-G-C is Benign according to our data. Variant chr2-166198690-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 246381.

BS2

High Homozygotes in GnomAd4 at 2 AD,SD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.5949C>G	p.Ser1983Arg	missense_variant	Exon 27 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.5949C>G	p.Ser1983Arg	missense_variant	Exon 27 of 27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.5949C>G	p.Ser1983Arg	missense_variant	Exon 27 of 27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.5916C>G	p.Ser1972Arg	missense_variant	Exon 27 of 27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.5916C>G	p.Ser1972Arg	missense_variant	Exon 27 of 27			ENSP00000495983.1	Q15858-4

Frequencies

GnomAD3 genomes

AF:

0.000257

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000870

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000781

AC:

AN:

230498

AF XY:

0.0000562

show subpopulations

Gnomad AFR exome

AF:

0.00107

Gnomad AMR exome

AF:

0.0000323

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000946

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000277

AC:

AN:

1441596

Hom.:

Cov.:

AF XY:

0.0000238

AC XY:

AN XY:

715484

show subpopulations

African (AFR)

AF:

0.000745

AC:

AN:

32202

American (AMR)

AF:

0.0000988

AC:

AN:

40502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25494

East Asian (EAS)

AF:

0.00

AC:

AN:

39548

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00000634

AC:

AN:

1104098

Other (OTH)

AF:

0.0000671

AC:

AN:

59586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000329

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41520

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.0000364

Hom.:

Bravo

AF:

0.000314

ESP6500AA

AF:

0.00106

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jul 29, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jul 28, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.21

.;T;.;.;T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.37

T;.;T;T;T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.025

T;T;T;T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

0.0

.;N;.;.;N;N

PhyloP100

1.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.63

N;.;.;.;.;N

REVEL

Uncertain

0.31

Sift

Benign

0.16

T;.;.;.;.;T

Sift4G

Benign

0.54

T;T;.;.;.;T

Vest4

0.043

MutPred

0.24

Loss of phosphorylation at S1972 (P = 4e-04);.;Loss of phosphorylation at S1972 (P = 4e-04);.;.;.;

MVP

0.67

MPC

0.13

ClinPred

0.022

GERP RS

4.6

Varity_R

0.19

gMVP

0.16

Mutation Taster

=63/37

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over