chr3-38739637-C-T

Position:

• chr3-38739637-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000449082.3(SCN10A):​c.2158G>A​(p.Asp720Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,692 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: 0.000012 (0 hom.)
• Consequence: SCN10A ENST00000449082.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.95

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.2158G>A	p.Asp720Asn	missense_variant	15/28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.2158G>A	p.Asp720Asn	missense_variant	15/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000655275.1	c.2185G>A	p.Asp729Asn	missense_variant	15/28			ENSP00000499510
SCN10A	ENST00000643924.1	c.2158G>A	p.Asp720Asn	missense_variant	14/27			ENSP00000495595	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251264 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 12, 2024

Variant summary: SCN10A c.2158G>A (p.Asp720Asn) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251264 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2158G>A in individuals affected with SCN10A-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 532067). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 720 of the SCN10A protein (p.Asp720Asn). This variant is present in population databases (rs781354273, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 532067). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Episodic pain syndrome, familial, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 05, 2022

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2022

The p.D720N variant (also known as c.2158G>A), located in coding exon 14 of the SCN10A gene, results from a G to A substitution at nucleotide position 2158. The aspartic acid at codon 720 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	0.0071	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.;M;.
MutationTaster	Benign	0.82	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.4	D;.;.;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.048	D;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.56
MutPred		0.50		Loss of ubiquitination at K715 (P = 0.1231);Loss of ubiquitination at K715 (P = 0.1231);Loss of ubiquitination at K715 (P = 0.1231);Loss of ubiquitination at K715 (P = 0.1231);
MVP		0.91
MPC		0.37
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.54
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -21

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

Publications

LitVar

Other links and lift over

dbSNP: rs781354273; hg19: chr3-38781128; COSMIC: COSV71862088;