rs145258166

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001365536.1(SCN9A):c.3329C>T(p.Ser1110Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,598,036 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. S1110P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000092 ( 1 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.56

Publications

4 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028585255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.3329C>T	p.Ser1110Leu	missense_variant	Exon 17 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN9A	ENST00000642356.2 link	c.3329C>T	p.Ser1110Leu	missense_variant	Exon 17 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11 link	c.3329C>T	p.Ser1110Leu	missense_variant	Exon 17 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5 link	c.3296C>T	p.Ser1099Leu	missense_variant	Exon 17 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1 link	c.3296C>T	p.Ser1099Leu	missense_variant	Exon 17 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes

AF:

0.000612

AC:

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000194

AC:

AN:

236918

AF XY:

0.000187

show subpopulations

Gnomad AFR exome

AF:

0.00249

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000280

Gnomad OTH exome

AF:

0.000520

GnomAD4 exome

AF:

0.0000920

AC:

133

AN:

1445958

Hom.:

Cov.:

AF XY:

0.0000934

AC XY:

AN XY:

717158

show subpopulations

African (AFR)

AF:

0.00229

AC:

AN:

33194

American (AMR)

AF:

0.000183

AC:

AN:

43620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25512

East Asian (EAS)

AF:

0.0000509

AC:

AN:

39274

South Asian (SAS)

AF:

0.0000593

AC:

AN:

84330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

1101680

Other (OTH)

AF:

0.000151

AC:

AN:

59780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000618

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

41502

American (AMR)

AF:

0.000197

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68000

Other (OTH)

AF:

0.000473

AC:

AN:

2112

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:

0.000130

Hom.:

Bravo

AF:

0.000771

ESP6500AA

AF:

0.00243

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000240

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Dec 27, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 04, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S1099L variant (also known as c.3296C>T), located in coding exon 16 of the SCN9A gene, results from a C to T substitution at nucleotide position 3296. The serine at codon 1099 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Benign:1

Jan 31, 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

0.098

BayesDel_addAF

Benign

-0.0090

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

.;D;.;.;D;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.029

T;T;T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

3.1

.;M;.;.;M;M

PhyloP100

9.6

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.6

D;.;.;.;.;D

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;.;.;.;.;D

Sift4G

Benign

0.11

T;T;.;.;.;T

Vest4

0.56

MVP

0.89

MPC

0.46

ClinPred

0.21

GERP RS

5.4

Varity_R

0.70

gMVP

0.33

Mutation Taster

=17/83

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over