Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 1P and 14B. PP3BP4_ModerateBP6_Very_StrongBS2

The NM_006514.4(SCN10A):c.308G>A(p.Arg103Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,826 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.91

Publications

5 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):

sodium channelopathy-related small fiber neuropathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
episodic pain syndrome, familial, 2
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
Brugada syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SCN10A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.21418944).

BP6

Variant 3-38792131-C-T is Benign according to our data. Variant chr3-38792131-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 532134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 56 AD,Unknown gene.

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
SCN10A	NM_006514.4	MANE Select	c.308G>A	p.Arg103Gln	missense	Exon 3 of 28	NP_006505.4
SCN10A	NM_001293306.2		c.308G>A	p.Arg103Gln	missense	Exon 2 of 27	NP_001280235.2
SCN10A	NM_001293307.2		c.308G>A	p.Arg103Gln	missense	Exon 2 of 26	NP_001280236.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.308G>A	p.Arg103Gln	missense	Exon 3 of 28	ENSP00000390600.2
SCN10A	ENST00000643924.1		c.308G>A	p.Arg103Gln	missense	Exon 2 of 27	ENSP00000495595.1
SCN10A	ENST00000655275.1		c.308G>A	p.Arg103Gln	missense	Exon 3 of 28	ENSP00000499510.1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000283

AC:

AN:

251020

AF XY:

0.000302

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000146

AC:

213

AN:

1461586

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

103

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.000537

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000702

AC:

AN:

1111804

Other (OTH)

AF:

0.000182

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.000368

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41556

American (AMR)

AF:

0.00144

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.0000775

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Brugada syndrome (1)

Cardiovascular phenotype (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.21

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

PhyloP100

7.9

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.61

MVP

0.97

MPC

0.40

ClinPred

0.33

GERP RS

4.2

Varity_R

0.68

gMVP

0.79

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over