rs145694222

chr3-38726851-C-Gchr3-38726851-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.2842G>C(p.Val948Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,614,072 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V948M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (1 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.346

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=0.038193822).
• BP6: Variant 3-38726851-C-G is Benign according to our data. Variant chr3-38726851-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407748.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=1}. Variant chr3-38726851-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.2842G>C	p.Val948Leu	missense_variant	17/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.2842G>C	p.Val948Leu	missense_variant	17/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.2869G>C	p.Val957Leu	missense_variant	17/28
SCN10A	ENST00000643924.1	c.2842G>C	p.Val948Leu	missense_variant	16/27			A1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000691

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000490 AC: 123 AN: 251218 Hom.: 1 AF XY: 0.000516 AC XY: 70 AN XY: 135754

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000899

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000841 AC: 1230 AN: 1461758 Hom.: 1 Cov.: 33 AF XY: 0.000820 AC XY: 596 AN XY: 727160

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000246

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: 0.00107

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74476

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000628 Hom.: 0

Bravo AF: 0.000533

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.00131

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SCN10A: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2019	This variant is associated with the following publications: (PMID: 28078312, 26220970) -

Episodic pain syndrome, familial, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Brugada syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 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	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	13
Dann	Benign	0.96
DEOGEN2	Benign	0.040	T;.;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.038	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.090	N;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.28	N;.;.;.
REVEL	Benign	0.16
Sift	Benign	0.29	T;.;.;.
Sift4G	Benign	0.42	T;.;.;.
Polyphen		0.12	B;.;B;.
Vest4		0.063
MutPred		0.70		Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);Loss of glycosylation at P952 (P = 0.0476);
MVP		0.62
MPC		0.061
ClinPred		0.0023	T
GERP RS		2.5
Varity_R		0.061
gMVP		0.11

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: rs145694222; hg19: chr3-38768342;