rs11711062

Variant names:

• chr3-38712241-A-T
• rs11711062
• NM_006514.4:c.4009T>A

Your query was ambiguous. Multiple possible variants found:

• chr3-38712241-A-T
• chr3-38712241-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006514.4(SCN10A):​c.4009T>A​(p.Ser1337Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,614,206 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (41 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.70
• Publications: 13 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060340464).
• BP6: Variant 3-38712241-A-T is Benign according to our data. Variant chr3-38712241-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00548 (8010/1461854) while in subpopulation MID AF = 0.0231 (133/5768). AF 95% confidence interval is 0.0199. There are 41 homozygotes in GnomAdExome4. There are 3919 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 673 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	NM_006514.4	MANE Select	c.4009T>A	p.Ser1337Thr	missense	Exon 23 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.4006T>A	p.Ser1336Thr	missense	Exon 22 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.3715T>A	p.Ser1239Thr	missense	Exon 21 of 26	NP_001280236.2	Q9Y5Y9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.4009T>A	p.Ser1337Thr	missense	Exon 23 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.4006T>A	p.Ser1336Thr	missense	Exon 22 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.4033T>A	p.Ser1345Thr	missense	Exon 23 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 675 AN: 152234 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00701

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00459 AC: 1154 AN: 251418 AF XY: 0.00461

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00719

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00548 AC: 8010 AN: 1461854 Hom.: 41 Cov.: 32 AF XY: 0.00539 AC XY: 3919 AN XY: 727228

African (AFR) AF: 0.00119 AC: 40 AN: 33474

American (AMR) AF: 0.00552 AC: 247 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00198 AC: 171 AN: 86258

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53420

Middle Eastern (MID) AF: 0.0231 AC: 133 AN: 5768

European-Non Finnish (NFE) AF: 0.00626 AC: 6962 AN: 1111982

Other (OTH) AF: 0.00575 AC: 347 AN: 60392

GnomAD4 genome AF: 0.00442 AC: 673 AN: 152352 Hom.: 5 Cov.: 33 AF XY: 0.00427 AC XY: 318 AN XY: 74506

African (AFR) AF: 0.00108 AC: 45 AN: 41588

American (AMR) AF: 0.00693 AC: 106 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00701 AC: 477 AN: 68026

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00654 Hom.: 2

Bravo AF: 0.00496

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00447 AC: 543

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00671

EpiControl AF: 0.00877

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	SCN10A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.010
DANN	Benign	0.26
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.90	L
PhyloP100		-3.7
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.18
Sift	Benign	0.57	T
Sift4G	Benign	0.43	T
Polyphen		0.059	B
Vest4		0.13
MVP		0.33
MPC		0.071
ClinPred		0.0074	T
GERP RS		-9.3
Varity_R		0.047
gMVP		0.27
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs11711062; hg19: chr3-38753732; COSMIC: COSV101479357;