rs114854233

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_001349253.2(SCN11A):c.4879T>C(p.Tyr1627His) variant causes a missense change. The variant allele was found at a frequency of 0.000202 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

SCN11A
NM_001349253.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.02

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 -8 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

BP6

Variant 3-38847191-A-G is Benign according to our data. Variant chr3-38847191-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474736.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 = 0.0000919 (14/152334) while in subpopulation NFE AF= 0.000162 (11/68024). AF 95% confidence interval is 0.0000905. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN11A	NM_001349253.2 link	c.4879T>C	p.Tyr1627His	missense_variant	Exon 30 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.4879T>C	p.Tyr1627His	missense_variant	Exon 30 of 30	5	NM_001349253.2	ENSP00000307599.3		Q9UI33-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000876

AC:

AN:

251026

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000213

AC:

312

AN:

1461802

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

156

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000275

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain:1

Dec 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1627 of the SCN11A protein (p.Tyr1627His). This variant is present in population databases (rs114854233, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SCN11A-related conditions. ClinVar contains an entry for this variant (Variation ID: 474736). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN11A protein function with a positive predictive value of 80%. 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. -

not specified

Benign:1

Dec 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN11A c.4879T>C (p.Tyr1627His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251026 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 190 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN11A causing Hereditary sensory and autonomic neuropathy type 7 phenotype (1e-06). c.4879T>C has been reported in the literature in an individual affected with Small-fiber neuropathy (Scheliga_2024). This report does not provide unequivocal conclusions about association of the variant with Hereditary sensory and autonomic neuropathy type 7. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 38211845). ClinVar contains an entry for this variant (Variation ID: 474736). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases

Benign:1

Sep 24, 2020

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

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.66

MVP

0.98

MPC

0.71

ClinPred

0.89

GERP RS

5.3

Varity_R

0.62

gMVP

0.50

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