chr3-38726809-T-C

Variant names:

• chr3-38726809-T-C
• rs57326399
• NM_006514.4:c.2884A>G

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.2884A>G​(p.Ile962Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,611,336 control chromosomes in the GnomAD database, including 50,977 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 0.21 (3920 hom., cov: 33)
  • Exomes 𝑓: 0.25 (47057 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.434
• Publications: 35 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=0.0023588836).
• BP6: Variant 3-38726809-T-C is Benign according to our data. Variant chr3-38726809-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	NM_006514.4	MANE Select	c.2884A>G	p.Ile962Val	missense	Exon 17 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.2884A>G	p.Ile962Val	missense	Exon 16 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.2590A>G	p.Ile864Val	missense	Exon 15 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.2884A>G	p.Ile962Val	missense	Exon 17 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.2884A>G	p.Ile962Val	missense	Exon 16 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.2911A>G	p.Ile971Val	missense	Exon 17 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32261 AN: 152016 Hom.: 3920 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.208

GnomAD2 exomes AF: 0.237 AC: 59575 AN: 251024 AF XY: 0.243

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.388

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.249 AC: 363364 AN: 1459202 Hom.: 47057 Cov.: 35 AF XY: 0.249 AC XY: 180778 AN XY: 725238

African (AFR) AF: 0.101 AC: 3386 AN: 33426

American (AMR) AF: 0.117 AC: 5214 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 8751 AN: 26124

East Asian (EAS) AF: 0.425 AC: 16835 AN: 39588

South Asian (SAS) AF: 0.235 AC: 20277 AN: 86220

European-Finnish (FIN) AF: 0.270 AC: 14419 AN: 53400

Middle Eastern (MID) AF: 0.224 AC: 1289 AN: 5760

European-Non Finnish (NFE) AF: 0.251 AC: 278702 AN: 1109770

Other (OTH) AF: 0.241 AC: 14491 AN: 60230

GnomAD4 genome AF: 0.212 AC: 32263 AN: 152134 Hom.: 3920 Cov.: 33 AF XY: 0.214 AC XY: 15908 AN XY: 74358

African (AFR) AF: 0.109 AC: 4513 AN: 41526

American (AMR) AF: 0.143 AC: 2193 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1192 AN: 3470

East Asian (EAS) AF: 0.403 AC: 2073 AN: 5148

South Asian (SAS) AF: 0.243 AC: 1166 AN: 4806

European-Finnish (FIN) AF: 0.269 AC: 2854 AN: 10600

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17477 AN: 67966

Other (OTH) AF: 0.206 AC: 434 AN: 2110

Alfa AF: 0.247 Hom.: 15758

Bravo AF: 0.198

TwinsUK AF: 0.249 AC: 925

ALSPAC AF: 0.242 AC: 934

ESP6500AA AF: 0.109 AC: 482

ESP6500EA AF: 0.262 AC: 2253

ExAC AF: 0.241 AC: 29240

Asia WGS AF: 0.268 AC: 935 AN: 3478

EpiCase AF: 0.246

EpiControl AF: 0.249

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	0.082
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.4
DANN	Benign	0.34
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.87	L
PhyloP100		0.43
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.19
Sift	Benign	0.12	T
Sift4G	Benign	0.53	T
Polyphen		0.44	B
Vest4		0.028
MPC		0.054
ClinPred		0.0097	T
GERP RS		-4.2
Varity_R		0.030
gMVP		0.13
Mutation Taster		=99/1	polymorphism (auto)

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: rs57326399; hg19: chr3-38768300; COSMIC: COSV71860512;