rs200965749

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP6

The NM_001365536.1(SCN9A):c.1979C>T(p.Thr660Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000637 in 1,600,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T660T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.82

Publications

3 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: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.75

BP6

Variant 2-166281804-G-A is Benign according to our data. Variant chr2-166281804-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 433098.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.1979C>T	p.Thr660Met	missense_variant	Exon 13 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.1979C>T	p.Thr660Met	missense_variant	Exon 13 of 27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.1979C>T	p.Thr660Met	missense_variant	Exon 13 of 27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.1946C>T	p.Thr649Met	missense_variant	Exon 13 of 27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.1946C>T	p.Thr649Met	missense_variant	Exon 13 of 27			ENSP00000495983.1	Q15858-4
SCN9A	ENST00000454569.6 link	c.1946C>T	p.Thr649Met	missense_variant	Exon 13 of 15	1		ENSP00000413212.2	A0A0C4DG82

Frequencies

GnomAD3 genomes

AF:

0.0000398

AC:

AN:

150628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000560

AC:

AN:

232288

AF XY:

0.0000317

show subpopulations

Gnomad AFR exome

AF:

0.000264

Gnomad AMR exome

AF:

0.0000326

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000589

Gnomad FIN exome

AF:

0.0000963

Gnomad NFE exome

AF:

0.0000465

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000662

AC:

AN:

1449838

Hom.:

Cov.:

AF XY:

0.0000763

AC XY:

AN XY:

720986

show subpopulations

African (AFR)

AF:

0.000153

AC:

AN:

32612

American (AMR)

AF:

0.0000238

AC:

AN:

42054

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25558

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39516

South Asian (SAS)

AF:

0.00

AC:

AN:

83588

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.0000776

AC:

AN:

1108070

Other (OTH)

AF:

0.0000334

AC:

AN:

59854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

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:

0.0000398

AC:

AN:

150628

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

73544

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

41044

American (AMR)

AF:

0.00

AC:

AN:

15072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67486

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000142

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000580

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Self-limited epilepsy with centrotemporal spikes

Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

CAADphred>15 -

Inborn genetic diseases

Uncertain:1

May 14, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T649M variant (also known as c.1946C>T), located in coding exon 12 of the SCN9A gene, results from a C to T substitution at nucleotide position 1946. The threonine at codon 649 is replaced by methionine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Oct 29, 2024

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

0.094

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;D;.;.;D;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;.;D;D;T;T;D

M_CAP

Uncertain

0.099

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.9

.;M;.;.;M;M;.

PhyloP100

3.8

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.5

D;.;.;.;.;D;.

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;.;.;.;.;D;.

Sift4G

Uncertain

0.018

D;T;.;.;.;T;.

Polyphen

0.55

.;P;.;.;P;.;.

Vest4

0.55

MVP

0.81

MPC

0.17

ClinPred

0.65

GERP RS

3.8

Varity_R

0.18

gMVP

0.63

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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