rs7617919

Variant names:

• chr3-38752498-G-A
• rs7617919
• NM_006514.4:c.1476C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006514.4(SCN10A):​c.1476C>T​(p.Leu492Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 1,588,222 control chromosomes in the GnomAD database, including 47,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3705 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43642 hom.)
• Consequence: SCN10A NM_006514.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.20
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-38752498-G-A is Benign according to our data. Variant chr3-38752498-G-A is described in ClinVar as Benign. ClinVar VariationId is 259992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.389 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.1476C>T	p.Leu492Leu	synonymous	Exon 12 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.1476C>T	p.Leu492Leu	synonymous	Exon 11 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.1462-2314C>T		intron	N/A	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.1476C>T	p.Leu492Leu	synonymous	Exon 12 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.1476C>T	p.Leu492Leu	synonymous	Exon 11 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.1503C>T	p.Leu501Leu	synonymous	Exon 12 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31307 AN: 152038 Hom.: 3705 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.233 AC: 53412 AN: 229124 AF XY: 0.239

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.389

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.241 AC: 346768 AN: 1436066 Hom.: 43642 Cov.: 33 AF XY: 0.242 AC XY: 172275 AN XY: 711868

African (AFR) AF: 0.101 AC: 3305 AN: 32636

American (AMR) AF: 0.112 AC: 4708 AN: 42204

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 8077 AN: 24656

East Asian (EAS) AF: 0.426 AC: 16537 AN: 38818

South Asian (SAS) AF: 0.234 AC: 19229 AN: 82294

European-Finnish (FIN) AF: 0.260 AC: 13703 AN: 52714

Middle Eastern (MID) AF: 0.218 AC: 1229 AN: 5640

European-Non Finnish (NFE) AF: 0.242 AC: 266092 AN: 1097946

Other (OTH) AF: 0.235 AC: 13888 AN: 59158

GnomAD4 genome AF: 0.206 AC: 31310 AN: 152156 Hom.: 3705 Cov.: 32 AF XY: 0.207 AC XY: 15411 AN XY: 74368

African (AFR) AF: 0.105 AC: 4351 AN: 41538

American (AMR) AF: 0.140 AC: 2143 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1173 AN: 3472

East Asian (EAS) AF: 0.403 AC: 2077 AN: 5150

South Asian (SAS) AF: 0.242 AC: 1166 AN: 4816

European-Finnish (FIN) AF: 0.259 AC: 2739 AN: 10576

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16879 AN: 67982

Other (OTH) AF: 0.200 AC: 423 AN: 2116

Alfa AF: 0.231 Hom.: 11769

Bravo AF: 0.193

Asia WGS AF: 0.270 AC: 940 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
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.3
DANN	Benign	0.64
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs7617919; hg19: chr3-38793989; COSMIC: COSV71860666;