NM_006514.4:c.3218T>C

Variant names:

• chr3-38725184-A-G
• rs6795970
• NM_006514.4:c.3218T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006514.4(SCN10A):​c.3218T>C​(p.Val1073Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,594,466 control chromosomes in the GnomAD database, including 318,682 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1073I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.70 (38763 hom., cov: 32)
  • Exomes 𝑓: 0.62 (279919 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.04
• Publications: 157 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=7.03869E-7).
• BP6: Variant 3-38725184-A-G is Benign according to our data. Variant chr3-38725184-A-G is described in ClinVar as Benign. ClinVar VariationId is 259996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	NM_006514.4	MANE Select	c.3218T>C	p.Val1073Ala	missense	Exon 18 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.3215T>C	p.Val1072Ala	missense	Exon 17 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.2924T>C	p.Val975Ala	missense	Exon 16 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.3218T>C	p.Val1073Ala	missense	Exon 18 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.3215T>C	p.Val1072Ala	missense	Exon 17 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.3242T>C	p.Val1081Ala	missense	Exon 18 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106402 AN: 151966 Hom.: 38689 Cov.: 32

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.664

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.653

GnomAD2 exomes AF: 0.652 AC: 161934 AN: 248186 AF XY: 0.644

Gnomad AFR exome AF: 0.911

Gnomad AMR exome AF: 0.688

Gnomad ASJ exome AF: 0.581

Gnomad EAS exome AF: 0.848

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.620

GnomAD4 exome AF: 0.619 AC: 893149 AN: 1442382 Hom.: 279919 Cov.: 45 AF XY: 0.618 AC XY: 442210 AN XY: 715412

African (AFR) AF: 0.917 AC: 30453 AN: 33202

American (AMR) AF: 0.686 AC: 30267 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 15049 AN: 25840

East Asian (EAS) AF: 0.851 AC: 33500 AN: 39346

South Asian (SAS) AF: 0.643 AC: 54279 AN: 84368

European-Finnish (FIN) AF: 0.549 AC: 29172 AN: 53116

Middle Eastern (MID) AF: 0.546 AC: 3076 AN: 5634

European-Non Finnish (NFE) AF: 0.601 AC: 659788 AN: 1097380

Other (OTH) AF: 0.632 AC: 37565 AN: 59398

GnomAD4 genome AF: 0.701 AC: 106542 AN: 152084 Hom.: 38763 Cov.: 32 AF XY: 0.699 AC XY: 51984 AN XY: 74352

African (AFR) AF: 0.907 AC: 37664 AN: 41512

American (AMR) AF: 0.678 AC: 10361 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2041 AN: 3470

East Asian (EAS) AF: 0.851 AC: 4402 AN: 5170

South Asian (SAS) AF: 0.664 AC: 3197 AN: 4812

European-Finnish (FIN) AF: 0.543 AC: 5733 AN: 10562

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.605 AC: 41082 AN: 67954

Other (OTH) AF: 0.655 AC: 1383 AN: 2110

Alfa AF: 0.636 Hom.: 150645

Bravo AF: 0.719

TwinsUK AF: 0.604 AC: 2239

ALSPAC AF: 0.596 AC: 2297

ESP6500AA AF: 0.899 AC: 3961

ESP6500EA AF: 0.602 AC: 5176

ExAC AF: 0.657 AC: 79802

Asia WGS AF: 0.771 AC: 2681 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Episodic pain syndrome, familial, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.66
DANN	Benign	0.54
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.060	T
MetaRNN	Benign	7.0e-7	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N
PhyloP100		-1.0
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0060
MPC		0.070
ClinPred		0.00070	T
GERP RS		-4.6
Varity_R		0.024
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6795970; hg19: chr3-38766675; COSMIC: COSV107530171;