rs141228634

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001349253.2(SCN11A):c.1744G>A(p.Ala582Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

SCN11A
NM_001349253.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.133

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06440991).

BP6

Variant 3-38903963-C-T is Benign according to our data. Variant chr3-38903963-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541582.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000118 (18/152276) while in subpopulation NFE AF= 0.00025 (17/68030). AF 95% confidence interval is 0.000159. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN11A	NM_001349253.2 link	c.1744G>A	p.Ala582Thr	missense_variant	Exon 16 of 30	ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9 link	c.1744G>A	p.Ala582Thr	missense_variant	Exon 16 of 30	5	NM_001349253.2	ENSP00000307599.3		Q9UI33-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251234

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

181

AN:

1461776

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000150

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000118

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000290

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 18, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30557356, 24776970, 26462871) -

Charcot-Marie-Tooth disease

Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Uncertain:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 582 of the SCN11A protein (p.Ala582Thr). This variant is present in population databases (rs141228634, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with painful peripheral neuropathy (PMID: 24776970). ClinVar contains an entry for this variant (Variation ID: 541582). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SCN11A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SCN11A function (PMID: 29213238). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Oct 02, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.099

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.064

T;T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

0.71

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.85

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.35

T;T;T

Sift4G

Benign

0.45

T;T;T

Polyphen

0.051

B;.;.

Vest4

0.11

MVP

0.86

MPC

0.15

ClinPred

0.045

GERP RS

4.7

Varity_R

0.15

gMVP

0.43

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