rs139861061

Positions:

• chr3-38728741-C-G
• chr3-38728741-C-T

Variant summary

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

The NM_006514.4(SCN10A):​c.2441G>C​(p.Arg814Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70

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=0.2887091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.2441G>C	p.Arg814Pro	missense_variant	16/28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.2441G>C	p.Arg814Pro	missense_variant	16/28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.2441G>C	p.Arg814Pro	missense_variant	15/27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.2468G>C	p.Arg823Pro	missense_variant	16/28			ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	0.16
DANN	Benign	0.93
DEOGEN2	Uncertain	0.58	D;.;D;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.32	.;T;T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.6	L;.;L;.
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.4	N;.;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.017	D;.;.;.
Sift4G	Benign	0.12	T;.;.;.
Polyphen		0.78	P;.;P;.
Vest4		0.48
MutPred		0.39		Gain of methylation at K818 (P = 0.0631);Gain of methylation at K818 (P = 0.0631);Gain of methylation at K818 (P = 0.0631);Gain of methylation at K818 (P = 0.0631);
MVP		0.61
MPC		0.19
ClinPred		0.49	T
GERP RS		-1.3
Varity_R		0.32
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139861061; hg19: chr3-38770232;