rs78953918

Positions:

chr3-38850578-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001349253.2(SCN11A):c.4230G>A(p.Thr1410=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,613,782 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 46 hom. )

Consequence

SCN11A
NM_001349253.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.301

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 3-38850578-C-T is Benign according to our data. Variant chr3-38850578-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38850578-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.301 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00483 (735/152156) while in subpopulation NFE AF= 0.00572 (389/68018). AF 95% confidence interval is 0.00525. There are 2 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 735 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN11A	NM_001349253.2 linkuse as main transcript	c.4230G>A	p.Thr1410=	synonymous_variant	29/30	ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9 linkuse as main transcript	c.4230G>A	p.Thr1410=	synonymous_variant	29/30	5	NM_001349253.2	ENSP00000307599	A2	Q9UI33-1

Frequencies

GnomAD3 genomes

AF:

0.00484

AC:

736

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.0152

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00573

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00613

AC:

1539

AN:

251082

Hom.:

AF XY:

0.00604

AC XY:

819

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00309

Gnomad ASJ exome

AF:

0.0161

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00510

Gnomad FIN exome

AF:

0.0164

Gnomad NFE exome

AF:

0.00613

Gnomad OTH exome

AF:

0.00702

GnomAD4 exome

AF:

0.00565

AC:

8252

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

4164

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00367

Gnomad4 ASJ exome

AF:

0.0156

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00485

Gnomad4 FIN exome

AF:

0.0164

Gnomad4 NFE exome

AF:

0.00536

Gnomad4 OTH exome

AF:

0.00586

GnomAD4 genome

AF:

0.00483

AC:

735

AN:

152156

Hom.:

Cov.:

AF XY:

0.00496

AC XY:

369

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00347

Gnomad4 ASJ

AF:

0.0164

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.0152

Gnomad4 NFE

AF:

0.00572

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00630

Hom.:

Bravo

AF:

0.00371

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SCN11A: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 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

BayesDel_noAF

Benign

-0.59

CADD

Benign

7.4

DANN

Benign

0.57

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