3-38894643-C-T

Position:

chr3-38894643-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001349253.2(SCN11A):c.2725G>A(p.Val909Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,770 control chromosomes in the GnomAD database, including 45,755 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. V909F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.20 ( 3478 hom., cov: 32)

Exomes 𝑓: 0.24 ( 42277 hom. )

Consequence

SCN11A
NM_001349253.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.51

Variant links:

Genes affected

SCN11A (HGNC:10583): (sodium voltage-gated channel alpha subunit 11) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is highly expressed in nociceptive neurons of dorsal root ganglia and trigeminal ganglia. It mediates brain-derived neurotrophic factor-evoked membrane depolarization and is a major effector of peripheral inflammatory pain hypersensitivity. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy type VII and familial episodic pain syndrome-3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2017]

SCN11A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076617897).

BP6

Variant 3-38894643-C-T is Benign according to our data. Variant chr3-38894643-C-T is described in ClinVar as [Benign]. Clinvar id is 260335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38894643-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN11A	NM_001349253.2 linkuse as main transcript	c.2725G>A	p.Val909Ile	missense_variant	19/30	ENST00000302328.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN11A	ENST00000302328.9 linkuse as main transcript	c.2725G>A	p.Val909Ile	missense_variant	19/30	5	NM_001349253.2	A2	Q9UI33-1

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30746

AN:

152026

Hom.:

3480

Cov.:

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.205

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.166

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.250

Gnomad OTH

AF:

0.203

GnomAD3 exomes

AF:

0.221

AC:

55576

AN:

251334

Hom.:

6539

AF XY:

0.221

AC XY:

29960

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.275

Gnomad ASJ exome

AF:

0.211

Gnomad EAS exome

AF:

0.120

Gnomad SAS exome

AF:

0.173

Gnomad FIN exome

AF:

0.241

Gnomad NFE exome

AF:

0.246

Gnomad OTH exome

AF:

0.235

GnomAD4 exome

AF:

0.236

AC:

345595

AN:

1461626

Hom.:

42277

Cov.:

AF XY:

0.235

AC XY:

170820

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.112

Gnomad4 AMR exome

AF:

0.272

Gnomad4 ASJ exome

AF:

0.213

Gnomad4 EAS exome

AF:

0.102

Gnomad4 SAS exome

AF:

0.178

Gnomad4 FIN exome

AF:

0.240

Gnomad4 NFE exome

AF:

0.249

Gnomad4 OTH exome

AF:

0.223

GnomAD4 genome

AF:

0.202

AC:

30753

AN:

152144

Hom.:

3478

Cov.:

AF XY:

0.202

AC XY:

15048

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.115

Gnomad4 AMR

AF:

0.238

Gnomad4 ASJ

AF:

0.205

Gnomad4 EAS

AF:

0.122

Gnomad4 SAS

AF:

0.166

Gnomad4 FIN

AF:

0.242

Gnomad4 NFE

AF:

0.250

Gnomad4 OTH

AF:

0.200

Alfa

AF:

0.231

Hom.:

6282

Bravo

AF:

0.200

TwinsUK

AF:

0.248

AC:

921

ALSPAC

AF:

0.241

AC:

930

ESP6500AA

AF:

0.126

AC:

553

ESP6500EA

AF:

0.245

AC:

2108

ExAC

AF:

0.219

AC:

26589

Asia WGS

AF:

0.139

AC:

483

AN:

3478

EpiCase

AF:

0.250

EpiControl

AF:

0.246

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Familial episodic pain syndrome with predominantly lower limb involvement

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Hereditary sensory and autonomic neuropathy type 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2018

This variant is associated with the following publications: (PMID: 27224030, 28953656) -

Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.0020

DANN

Benign

0.56

DEOGEN2

Benign

0.051

T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0085

LIST_S2

Benign

0.27

T;T;T

MetaRNN

Benign

0.0077

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

N;N;N

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.24

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.64

T;T;T

Sift4G

Benign

0.70

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.040

MPC

0.11

ClinPred

0.011

GERP RS

-9.1

Varity_R

0.012

gMVP

0.076

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