rs1060501717

Variant names:

• chr3-38793768-A-T
• rs1060501717
• NM_006514.4:c.243T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006514.4(SCN10A):​c.243T>A​(p.Asp81Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.254

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.243T>A	p.Asp81Glu	missense_variant	Exon 2 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.243T>A	p.Asp81Glu	missense_variant	Exon 2 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.243T>A	p.Asp81Glu	missense_variant	Exon 1 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.243T>A	p.Asp81Glu	missense_variant	Exon 2 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome Uncertain:1

Aug 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with glutamic acid at codon 81 of the SCN10A protein (p.Asp81Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN10A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Nov 02, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Asp81Glu (c.243T>A) in SCN10A Seen in a family with familial DCM in our center, with a likely pathogenic DSP variant. Testing done at Invitae. This gene has no well-established disease association. As such, we would by default consider it a variant of uncertain significance. We did not review it. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	8.3
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;D;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.92	.;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.1	M;.;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.5	D;.;.;.
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Benign	0.17	T;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.49
MutPred		0.41		Gain of glycosylation at Y86 (P = 0.0118);Gain of glycosylation at Y86 (P = 0.0118);Gain of glycosylation at Y86 (P = 0.0118);Gain of glycosylation at Y86 (P = 0.0118);
MVP		0.76
MPC		0.37
ClinPred		0.99	D
GERP RS		-3.7
Varity_R		0.69
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060501717; hg19: chr3-38835259;