Genetic Variant SCN10A:p.Thr1131Thr (chr3-38722372-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006514.4(SCN10A):c.3393C>G(p.Thr1131Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,744 control chromosomes in the GnomAD database, including 51,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1131T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.22 ( 4092 hom., cov: 32)

Exomes 𝑓: 0.25 ( 47339 hom. )

Consequence

SCN10A
NM_006514.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.553

Publications

21 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
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

new If you want to explore the variant's impact on the transcript NM_006514.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 3-38722372-G-C is Benign according to our data. Variant chr3-38722372-G-C is described in ClinVar as Benign. ClinVar VariationId is 259998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.553 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 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.3393C>G	p.Thr1131Thr	synonymous	Exon 20 of 28	NP_006505.4	Q9Y5Y9
SCN10A	NM_001293306.2		c.3390C>G	p.Thr1130Thr	synonymous	Exon 19 of 27	NP_001280235.2	Q9Y5Y9
SCN10A	NM_001293307.2		c.3099C>G	p.Thr1033Thr	synonymous	Exon 18 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.3393C>G	p.Thr1131Thr	synonymous	Exon 20 of 28	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1		c.3390C>G	p.Thr1130Thr	synonymous	Exon 19 of 27	ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1		c.3417C>G	p.Thr1139Thr	synonymous	Exon 20 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33546

AN:

151952

Hom.:

4092

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.374

Gnomad AMR

AF:

0.149

Gnomad ASJ

AF:

0.340

Gnomad EAS

AF:

0.402

Gnomad SAS

AF:

0.241

Gnomad FIN

AF:

0.273

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.216

GnomAD2 exomes

AF:

0.239

AC:

60154

AN:

251362

AF XY:

0.244

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.335

Gnomad EAS exome

AF:

0.388

Gnomad FIN exome

AF:

0.270

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.243

GnomAD4 exome

AF:

0.250

AC:

365387

AN:

1461674

Hom.:

47339

Cov.:

AF XY:

0.250

AC XY:

181821

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.130

AC:

4341

AN:

33480

American (AMR)

AF:

0.120

AC:

5379

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.332

AC:

8672

AN:

26132

East Asian (EAS)

AF:

0.437

AC:

17338

AN:

39698

South Asian (SAS)

AF:

0.234

AC:

20148

AN:

86248

European-Finnish (FIN)

AF:

0.273

AC:

14554

AN:

53388

Middle Eastern (MID)

AF:

0.229

AC:

1321

AN:

5768

European-Non Finnish (NFE)

AF:

0.251

AC:

278897

AN:

1111854

Other (OTH)

AF:

0.244

AC:

14737

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

14559

29119

43678

58238

72797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9422

18844

28266

37688

47110

<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:

33555

AN:

152070

Hom.:

4092

Cov.:

AF XY:

0.223

AC XY:

16542

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.138

AC:

5719

AN:

41492

American (AMR)

AF:

0.149

AC:

2275

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

1180

AN:

3468

East Asian (EAS)

AF:

0.403

AC:

2081

AN:

5166

South Asian (SAS)

AF:

0.242

AC:

1162

AN:

4810

European-Finnish (FIN)

AF:

0.273

AC:

2879

AN:

10562

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:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

1345

2689

4034

5378

6723

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:

0.255

Hom.:

1746

Bravo

AF:

0.208

Asia WGS

AF:

0.272

AC:

947

AN:

3478

EpiCase

AF:

0.247

EpiControl

AF:

0.248

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

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

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.57

(source)

DANN

Benign

0.28

PhyloP100

0.55

Mutation Taster

=100/0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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