chr3-38755796-G-A

Position:

chr3-38755796-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006514.4(SCN10A):c.1453C>T(p.Arg485Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,613,580 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R485H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

SCN10A
NM_006514.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.70

Variant links:

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]

SCN10A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067727566).

BP6

Variant 3-38755796-G-A is Benign according to our data. Variant chr3-38755796-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38755796-G-A is described in Lovd as [Benign]. Variant chr3-38755796-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 306 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4 linkuse as main transcript	c.1453C>T	p.Arg485Cys	missense_variant	11/28	ENST00000449082.3	NP_006505.4	Q9Y5Y9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN10A	ENST00000449082.3 linkuse as main transcript	c.1453C>T	p.Arg485Cys	missense_variant	11/28	1	NM_006514.4	ENSP00000390600.2	Q9Y5Y9
SCN10A	ENST00000643924.1 linkuse as main transcript	c.1453C>T	p.Arg485Cys	missense_variant	10/27			ENSP00000495595.1	A0A2R8Y6J6
SCN10A	ENST00000655275.1 linkuse as main transcript	c.1480C>T	p.Arg494Cys	missense_variant	11/28			ENSP00000499510.1	A0A590UJM0

Frequencies

GnomAD3 genomes

AF:

0.00201

AC:

306

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00715

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000493

AC:

124

AN:

251390

Hom.:

AF XY:

0.000375

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00689

Gnomad AMR exome

AF:

0.000260

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000179

AC:

261

AN:

1461368

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

109

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.00678

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.00201

AC:

306

AN:

152212

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00713

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000371

Hom.:

Bravo

AF:

0.00219

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000700

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2013	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2021	This variant is associated with the following publications: (PMID: 28078312, 28407228) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Brugada syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 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

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;.;D;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

.;T;T;T

M_CAP

Benign

0.080

MetaRNN

Benign

0.0068

T;T;T;T

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.4

L;.;L;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.1

N;.;.;.

REVEL

Uncertain

0.49

Sift

Uncertain

0.0060

D;.;.;.

Sift4G

Benign

0.066

T;.;.;.

Polyphen

0.98

D;.;D;.

Vest4

0.47

MVP

0.98

MPC

0.29

ClinPred

0.049

GERP RS

4.8

Varity_R

0.12

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over