3-38907980-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001349253.2(SCN11A):c.1442G>A(p.Gly481Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,608,770 control chromosomes in the GnomAD database, including 793 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G481A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.025 ( 72 hom., cov: 32)

Exomes 𝑓: 0.028 ( 721 hom. )

Consequence

SCN11A
NM_001349253.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.325

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant hereditary sensory and autonomic neuropathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
familial episodic pain syndrome with predominantly lower limb involvement
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
hereditary sensory and autonomic neuropathy type 7
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
sodium channelopathy-related small fiber neuropathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SCN11A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023756325).

BP6

Variant 3-38907980-C-T is Benign according to our data. Variant chr3-38907980-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN11A	NM_001349253.2 link	c.1442G>A	p.Gly481Glu	missense_variant	Exon 14 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.1442G>A	p.Gly481Glu	missense_variant	Exon 14 of 30	5	NM_001349253.2	ENSP00000307599.3		Q9UI33-1

Frequencies

GnomAD3 genomes

AF:

0.0250

AC:

3808

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00570

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0488

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0644

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0293

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.0318

AC:

7812

AN:

245726

AF XY:

0.0300

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.0722

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.00116

Gnomad FIN exome

AF:

0.0639

Gnomad NFE exome

AF:

0.0291

Gnomad OTH exome

AF:

0.0283

GnomAD4 exome

AF:

0.0278

AC:

40462

AN:

1456590

Hom.:

721

Cov.:

AF XY:

0.0272

AC XY:

19711

AN XY:

724264

show subpopulations

African (AFR)

AF:

0.00436

AC:

144

AN:

33036

American (AMR)

AF:

0.0672

AC:

2922

AN:

43498

Ashkenazi Jewish (ASJ)

AF:

0.0143

AC:

373

AN:

26036

East Asian (EAS)

AF:

0.00164

AC:

AN:

39636

South Asian (SAS)

AF:

0.0130

AC:

1093

AN:

84318

European-Finnish (FIN)

AF:

0.0630

AC:

3362

AN:

53362

Middle Eastern (MID)

AF:

0.00696

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0280

AC:

31066

AN:

1110750

Other (OTH)

AF:

0.0232

AC:

1397

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1801

3601

5402

7202

9003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0250

AC:

3809

AN:

152180

Hom.:

Cov.:

AF XY:

0.0268

AC XY:

1997

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00568

AC:

236

AN:

41536

American (AMR)

AF:

0.0487

AC:

745

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3468

East Asian (EAS)

AF:

0.00290

AC:

AN:

5180

South Asian (SAS)

AF:

0.0114

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0644

AC:

681

AN:

10574

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0293

AC:

1991

AN:

68004

Other (OTH)

AF:

0.0142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

192

384

577

769

961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0259

Hom.:

234

Bravo

AF:

0.0226

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.0250

AC:

215

ExAC

AF:

0.0306

AC:

3709

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0251

EpiControl

AF:

0.0231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Nov 27, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.055

T;.;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.62

T;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Uncertain

-0.068

MutationAssessor

Benign

1.0

L;L;L

PhyloP100

0.33

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.46

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.25

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.96

D;.;.

Vest4

0.043

MPC

0.19

ClinPred

0.011

GERP RS

0.62

Varity_R

0.054

gMVP

0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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3-38907980-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over