3-38756680-C-T

Variant names:

• chr3-38756680-C-T
• rs62244070
• NM_006514.4:c.1284G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006514.4(SCN10A):​c.1284G>A​(p.Glu428Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,612,192 control chromosomes in the GnomAD database, including 47,700 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3662 hom., cov: 31)
  • Exomes 𝑓: 0.24 (44038 hom.)
• Consequence: SCN10A NM_006514.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.490
• Publications: 17 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 3-38756680-C-T is Benign according to our data. Variant chr3-38756680-C-T is described in ClinVar as Benign. ClinVar VariationId is 259991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.387 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.1284G>A	p.Glu428Glu	synonymous	Exon 10 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.1284G>A	p.Glu428Glu	synonymous	Exon 9 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.1284G>A	p.Glu428Glu	synonymous	Exon 9 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.1284G>A	p.Glu428Glu	synonymous	Exon 10 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.1284G>A	p.Glu428Glu	synonymous	Exon 9 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.1311G>A	p.Glu437Glu	synonymous	Exon 10 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31127 AN: 151958 Hom.: 3662 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.231 AC: 57831 AN: 250870 AF XY: 0.236

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.330

Gnomad EAS exome AF: 0.391

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.240 AC: 350749 AN: 1460116 Hom.: 44038 Cov.: 33 AF XY: 0.241 AC XY: 174949 AN XY: 726506

African (AFR) AF: 0.101 AC: 3375 AN: 33466

American (AMR) AF: 0.111 AC: 4960 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 8554 AN: 26122

East Asian (EAS) AF: 0.427 AC: 16934 AN: 39690

South Asian (SAS) AF: 0.234 AC: 20171 AN: 86228

European-Finnish (FIN) AF: 0.259 AC: 13711 AN: 52984

Middle Eastern (MID) AF: 0.217 AC: 1230 AN: 5672

European-Non Finnish (NFE) AF: 0.241 AC: 267712 AN: 1110874

Other (OTH) AF: 0.234 AC: 14102 AN: 60356

GnomAD4 genome AF: 0.205 AC: 31130 AN: 152076 Hom.: 3662 Cov.: 31 AF XY: 0.206 AC XY: 15315 AN XY: 74318

African (AFR) AF: 0.104 AC: 4327 AN: 41514

American (AMR) AF: 0.138 AC: 2116 AN: 15290

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

East Asian (EAS) AF: 0.402 AC: 2072 AN: 5160

South Asian (SAS) AF: 0.242 AC: 1162 AN: 4804

European-Finnish (FIN) AF: 0.258 AC: 2723 AN: 10554

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16778 AN: 67964

Other (OTH) AF: 0.200 AC: 422 AN: 2114

Alfa AF: 0.223 Hom.: 3042

Bravo AF: 0.192

Asia WGS AF: 0.270 AC: 940 AN: 3478

EpiCase AF: 0.238

EpiControl AF: 0.239

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	-0.39
CADD	Benign	3.2
DANN	Benign	0.48
PhyloP100		-0.49
Mutation Taster		=100/0	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: rs62244070; hg19: chr3-38798171; COSMIC: COSV71861138;