NM_006514.4:c.3275T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006514.4(SCN10A):c.3275T>C(p.Leu1092Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,611,844 control chromosomes in the GnomAD database, including 51,330 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4103 hom., cov: 33)

Exomes 𝑓: 0.25 ( 47227 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.776

Publications

58 publications found

Variant links:

Genes affected

SCN10A (HGNC:10582): (sodium voltage-gated channel alpha subunit 10) The protein encoded by this gene is a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit. The properties of the channel formed by the encoded transmembrane protein can be altered by interaction with different beta subunits. This protein may be involved in the onset of pain associated with peripheral neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

SCN10A Gene-Disease associations (from GenCC):

episodic pain syndrome, familial, 2
Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
sodium channelopathy-related small fiber neuropathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

SCN10A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020908415).

BP6

Variant 3-38723507-A-G is Benign according to our data. Variant chr3-38723507-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006514.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN10A	NM_006514.4	MANE Select	c.3275T>C	p.Leu1092Pro	missense	Exon 19 of 28	NP_006505.4	Q9Y5Y9
SCN10A	NM_001293306.2		c.3272T>C	p.Leu1091Pro	missense	Exon 18 of 27	NP_001280235.2	Q9Y5Y9
SCN10A	NM_001293307.2		c.2981T>C	p.Leu994Pro	missense	Exon 17 of 26	NP_001280236.2	Q9Y5Y9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.3275T>C	p.Leu1092Pro	missense	Exon 19 of 28	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1		c.3272T>C	p.Leu1091Pro	missense	Exon 18 of 27	ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1		c.3299T>C	p.Leu1100Pro	missense	Exon 19 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33587

AN:

152066

Hom.:

4103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.373

Gnomad AMR

AF:

0.149

Gnomad ASJ

AF:

0.341

Gnomad EAS

AF:

0.403

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.273

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.216

GnomAD2 exomes

AF:

0.240

AC:

58530

AN:

243924

AF XY:

0.245

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.335

Gnomad EAS exome

AF:

0.389

Gnomad FIN exome

AF:

0.271

Gnomad NFE exome

AF:

0.259

Gnomad OTH exome

AF:

0.243

GnomAD4 exome

AF:

0.250

AC:

364980

AN:

1459660

Hom.:

47227

Cov.:

AF XY:

0.250

AC XY:

181556

AN XY:

725990

show subpopulations

African (AFR)

AF:

0.130

AC:

4341

AN:

33460

American (AMR)

AF:

0.121

AC:

5363

AN:

44454

Ashkenazi Jewish (ASJ)

AF:

0.332

AC:

8663

AN:

26108

East Asian (EAS)

AF:

0.437

AC:

17309

AN:

39632

South Asian (SAS)

AF:

0.233

AC:

20050

AN:

85976

European-Finnish (FIN)

AF:

0.273

AC:

14535

AN:

53312

Middle Eastern (MID)

AF:

0.229

AC:

1318

AN:

5766

European-Non Finnish (NFE)

AF:

0.251

AC:

278670

AN:

1110636

Other (OTH)

AF:

0.244

AC:

14731

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

13815

27630

41444

55259

69074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9418

18836

28254

37672

47090

<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:

0.221

AC:

33596

AN:

152184

Hom.:

4103

Cov.:

AF XY:

0.223

AC XY:

16583

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.138

AC:

5737

AN:

41540

American (AMR)

AF:

0.149

AC:

2279

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.341

AC:

1183

AN:

3470

East Asian (EAS)

AF:

0.403

AC:

2085

AN:

5168

South Asian (SAS)

AF:

0.241

AC:

1159

AN:

4816

European-Finnish (FIN)

AF:

0.273

AC:

2894

AN:

10596

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.256

AC:

17404

AN:

67978

Other (OTH)

AF:

0.214

AC:

452

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1368

2735

4103

5470

6838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.245

Hom.:

22171

Bravo

AF:

0.209

TwinsUK

AF:

0.250

AC:

926

ALSPAC

AF:

0.241

AC:

928

ESP6500AA

AF:

0.142

AC:

625

ESP6500EA

AF:

0.260

AC:

2236

ExAC

AF:

0.241

AC:

29298

Asia WGS

AF:

0.272

AC:

946

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Brugada syndrome (1)

Cardiovascular phenotype (1)

Episodic pain syndrome, familial, 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.036

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.72

PhyloP100

-0.78

PrimateAI

Benign

0.30

PROVEAN

Benign

3.2

REVEL

Benign

0.18

Sift

Benign

0.60

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.013

MPC

0.092

ClinPred

0.0018

GERP RS

-0.53

Varity_R

0.087

gMVP

0.40

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