3-38763514-C-A

Position:

• chr3-38763514-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006514.4(SCN10A):​c.682G>T​(p.Val228Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 0.0000014 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.682G>T	p.Val228Leu	missense_variant	6/28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.682G>T	p.Val228Leu	missense_variant	6/28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.682G>T	p.Val228Leu	missense_variant	5/27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.682G>T	p.Val228Leu	missense_variant	6/28			ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251350 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461268 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;.;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	D;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	D;.;.;.
Sift4G	Benign	0.16	T;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.53
MutPred		0.80		Gain of ubiquitination at K224 (P = 0.1128);Gain of ubiquitination at K224 (P = 0.1128);Gain of ubiquitination at K224 (P = 0.1128);Gain of ubiquitination at K224 (P = 0.1128);
MVP		0.91
MPC		0.30
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.65
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs141368548; hg19: chr3-38805005;