rs201106879

Variant names:

• chr3-38726623-C-T
• rs201106879
• NM_006514.4:c.3070G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006514.4(SCN10A):​c.3070G>A​(p.Val1024Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000566 in 1,590,064 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.333
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028200984).
• BS2: High AC in GnomAdExome4 at 5 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.3070G>A	p.Val1024Met	missense	Exon 17 of 28	NP_006505.4	Q9Y5Y9
	SCN10A	NM_001293306.2		c.3070G>A	p.Val1024Met	missense	Exon 16 of 27	NP_001280235.2	Q9Y5Y9
	SCN10A	NM_001293307.2		c.2776G>A	p.Val926Met	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.3070G>A	p.Val1024Met	missense	Exon 17 of 28	ENSP00000390600.2	Q9Y5Y9
	SCN10A	ENST00000643924.1		c.3070G>A	p.Val1024Met	missense	Exon 16 of 27	ENSP00000495595.1	A0A2R8Y6J6
	SCN10A	ENST00000655275.1		c.3097G>A	p.Val1033Met	missense	Exon 17 of 28	ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000206 AC: 5 AN: 243042 AF XY: 0.0000230

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000878

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1437718 Hom.: 0 Cov.: 30 AF XY: 0.00000282 AC XY: 2 AN XY: 710344

African (AFR) AF: 0.0000905 AC: 3 AN: 33152

American (AMR) AF: 0.0000453 AC: 2 AN: 44104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 39134

South Asian (SAS) AF: 0.00 AC: 0 AN: 83456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094792

Other (OTH) AF: 0.00 AC: 0 AN: 59264

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74496

African (AFR) AF: 0.0000721 AC: 3 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Brugada syndrome (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.028	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.33
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.15
Sift	Benign	0.12	T
Sift4G	Benign	0.10	T
Polyphen		0.012	B
Vest4		0.094
MutPred		0.27		Loss of glycosylation at K1027 (P = 0.0202)
MVP		0.53
MPC		0.064
ClinPred		0.037	T
GERP RS		1.8
Varity_R		0.043
gMVP		0.17
Mutation Taster		=97/3	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: rs201106879; hg19: chr3-38768114;