rs202040659

chr3-38701944-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006514.4(SCN10A):c.4552G>A(p.Val1518Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1518V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0330

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05631557).
• BP6: Variant 3-38701944-C-T is Benign according to our data. Variant chr3-38701944-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 532075.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr3-38701944-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.4552G>A	p.Val1518Ile	missense_variant	27/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.4552G>A	p.Val1518Ile	missense_variant	27/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.4576G>A	p.Val1526Ile	missense_variant	27/28
SCN10A	ENST00000643924.1	c.4549G>A	p.Val1517Ile	missense_variant	26/27			A1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000717 AC: 18 AN: 251220 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135754

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727212

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74460

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000793 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2020

Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 532075; Landrum et al., 2016); Functional studies suggest this variant affects sodium channel function (Gando et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31195250) -

Brugada syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	15
Dann	Benign	0.36
DEOGEN2	Benign	0.39	T;.;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.067	N
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.056	T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	-0.68	N;.;N;.
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.45	N;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.94	T;.;.;.
Sift4G	Benign	1.0	T;.;.;.
Polyphen		0.90	P;.;P;.
Vest4		0.26
MVP		0.58
MPC		0.10
ClinPred		0.046	T
GERP RS		3.8
Varity_R		0.033
gMVP		0.14

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: rs202040659; hg19: chr3-38743435;