rs6599241

Positions:

• chr3-38698083-T-A
• chr3-38698083-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006514.4(SCN10A):​c.5137A>T​(p.Met1713Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1713V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41059425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.5137A>T	p.Met1713Leu	missense_variant	28/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.5137A>T	p.Met1713Leu	missense_variant	28/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.5161A>T	p.Met1721Leu	missense_variant	28/28
SCN10A	ENST00000643924.1	c.5134A>T	p.Met1712Leu	missense_variant	27/27			A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T;.;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	.;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	-0.21	N;.;N;.
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.0	N;.;.;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.036	D;.;.;.
Polyphen		0.0010	B;.;B;.
Vest4		0.24
MutPred		0.57		Gain of catalytic residue at M1713 (P = 0.0175);Gain of catalytic residue at M1713 (P = 0.0175);Gain of catalytic residue at M1713 (P = 0.0175);.;
MVP		0.67
MPC		0.056
ClinPred		0.90	D
GERP RS		5.4
Varity_R		0.47
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs6599241; hg19: chr3-38739574;