rs77804526

chr3-38698131-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006514.4(SCN10A):c.5089G>A(p.Val1697Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,082 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1697A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0090 (8 hom., cov: 31)
  • Exomes 𝑓: 0.013 (170 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.352

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009874433).
• BP6: Variant 3-38698131-C-T is Benign according to our data. Variant chr3-38698131-C-T is described in ClinVar as [Benign]. Clinvar id is 240679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38698131-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00899 (1368/152218) while in subpopulation SAS AF= 0.022 (106/4810). AF 95% confidence interval is 0.0186. There are 8 homozygotes in gnomad4. There are 665 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1365 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.5089G>A	p.Val1697Ile	missense_variant	28/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.5089G>A	p.Val1697Ile	missense_variant	28/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.5113G>A	p.Val1705Ile	missense_variant	28/28
SCN10A	ENST00000643924.1	c.5086G>A	p.Val1696Ile	missense_variant	27/27			A1

Frequencies

GnomAD3 genomes AF: 0.00897 AC: 1365 AN: 152100 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00721

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0216

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0117 AC: 2930 AN: 251324 Hom.: 28 AF XY: 0.0130 AC XY: 1772 AN XY: 135830

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0243

Gnomad FIN exome AF: 0.00480

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0129 AC: 18887 AN: 1461864 Hom.: 170 Cov.: 91 AF XY: 0.0135 AC XY: 9809 AN XY: 727232

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.00570

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.0260

Gnomad4 FIN exome AF: 0.00534

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.00899 AC: 1368 AN: 152218 Hom.: 8 Cov.: 31 AF XY: 0.00894 AC XY: 665 AN XY: 74420

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.00720

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0220

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.0131

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0123 Hom.: 17

Bravo AF: 0.00855

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0137 AC: 118

ExAC AF: 0.0123 AC: 1496

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0162

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

SCN10A: BS1, BS2 -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2018

This alteration is classified as 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	0.093
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	11
Dann	Benign	0.70
DEOGEN2	Uncertain	0.45	T;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.058	N
MetaRNN	Benign	0.0099	T;T;T;T
MetaSVM	Uncertain	-0.027	T
MutationAssessor	Benign	0.20	N;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.74	N;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.24	T;.;.;.
Sift4G	Benign	0.68	T;.;.;.
Polyphen		0.024	B;.;B;.
Vest4		0.037
MPC		0.052
ClinPred		0.00089	T
GERP RS		0.24
Varity_R		0.060
gMVP		0.56

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: rs77804526; hg19: chr3-38739622;