3-38697368-A-C

Variant names:

• chr3-38697368-A-C
• NM_006514.4:c.5852T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006514.4(SCN10A):​c.5852T>G​(p.Leu1951Arg) 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 (★). Synonymous variant affecting the same amino acid position (i.e. L1951L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.784
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09262216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.5852T>G	p.Leu1951Arg	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.5852T>G	p.Leu1951Arg	missense_variant	Exon 28 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.5849T>G	p.Leu1950Arg	missense_variant	Exon 27 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.5876T>G	p.Leu1959Arg	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

Apr 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L1951R variant (also known as c.5852T>G), located in coding exon 27 of the SCN10A gene, results from a T to G substitution at nucleotide position 5852. The leucine at codon 1951 is replaced by arginine, an amino acid with dissimilar 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 variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.8
DANN	Benign	0.71
DEOGEN2	Benign	0.042	T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.22	.;T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.093	T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.0	N;.;N;.
PhyloP100		-0.78
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.090	N;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.051	T;.;.;.
Sift4G	Uncertain	0.014	D;.;.;.
Polyphen		0.090	B;.;B;.
Vest4		0.036
MutPred		0.15		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		0.26
MPC		0.086
ClinPred		0.10	T
GERP RS		-1.1
Varity_R		0.083
gMVP		0.38
Mutation Taster		=99/1	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: chr3-38738859;