3-38697363-C-A

Variant names:

• chr3-38697363-C-A
• NM_006514.4:c.5857G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006514.4(SCN10A):​c.5857G>T​(p.Ala1953Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1953V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.71
• 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):

• sodium channelopathy-related small fiber neuropathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• episodic pain syndrome, familial, 2

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• Brugada syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052832663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.5857G>T	p.Ala1953Ser	missense_variant	Exon 28 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.5857G>T	p.Ala1953Ser	missense_variant	Exon 28 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.5854G>T	p.Ala1952Ser	missense_variant	Exon 27 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.5881G>T	p.Ala1961Ser	missense_variant	Exon 28 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Feb 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A1953S variant (also known as c.5857G>T), located in coding exon 27 of the SCN10A gene, results from a G to T substitution at nucleotide position 5857. The alanine at codon 1953 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.024
DANN	Benign	0.19
DEOGEN2	Benign	0.044	T;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.23	.;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.053	T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.0	N;.;N;.
PhyloP100		-1.7
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.0	N;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.54	T;.;.;.
Sift4G	Benign	0.32	T;.;.;.
Polyphen		0.0010	B;.;B;.
Vest4		0.032
MutPred		0.083		Gain of glycosylation at S1948 (P = 0.0092);Gain of glycosylation at S1948 (P = 0.0092);Gain of glycosylation at S1948 (P = 0.0092);.;
MVP		0.35
MPC		0.056
ClinPred		0.040	T
GERP RS		-1.4
Varity_R		0.033
gMVP		0.30
Mutation Taster		=98/2	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

hg19: chr3-38738854;