chr3-38697411-A-G

Position:

• chr3-38697411-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006514.4(SCN10A):​c.5809T>C​(p.Ser1937Pro) 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. 12/21 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. S1937C) 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: 1.02

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19936442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.5809T>C	p.Ser1937Pro	missense_variant	28/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.5809T>C	p.Ser1937Pro	missense_variant	28/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.5833T>C	p.Ser1945Pro	missense_variant	28/28
SCN10A	ENST00000643924.1	c.5806T>C	p.Ser1936Pro	missense_variant	27/27			A1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2022

The p.S1937P variant (also known as c.5809T>C), located in coding exon 27 of the SCN10A gene, results from a T to C substitution at nucleotide position 5809. The serine at codon 1937 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;T;.
Eigen	Benign	0.083
Eigen_PC	Benign	0.074
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.57	.;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	0.0	N;.;N;.
MutationTaster	Benign	0.51	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N;.;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D;.;.;.
Sift4G	Uncertain	0.025	D;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.15
MutPred		0.15		Gain of glycosylation at S1937 (P = 0.0193);Gain of glycosylation at S1937 (P = 0.0193);Gain of glycosylation at S1937 (P = 0.0193);.;
MVP		0.88
MPC		0.082
ClinPred		0.85	D
GERP RS		4.2
Varity_R		0.37
gMVP		0.32

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-38738902;