3-38883320-G-C

Position:

chr3-38883320-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001349253.2(SCN11A):c.3132C>G(p.Asn1044Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,948 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 5 hom. )

Consequence

SCN11A
NM_001349253.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.18

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=0.017271906).

BP6

Variant 3-38883320-G-C is Benign according to our data. Variant chr3-38883320-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 474718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38883320-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00361 (550/152248) while in subpopulation AFR AF= 0.0118 (491/41544). AF 95% confidence interval is 0.011. There are 3 homozygotes in gnomad4. There are 258 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 550 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN11A	NM_001349253.2 linkuse as main transcript	c.3132C>G	p.Asn1044Lys	missense_variant	22/30	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.3132C>G	p.Asn1044Lys	missense_variant	22/30	5	NM_001349253.2	ENSP00000307599	A2	Q9UI33-1

Frequencies

GnomAD3 genomes

AF:

0.00353

AC:

537

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00113

AC:

283

AN:

251240

Hom.:

AF XY:

0.000759

AC XY:

103

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000754

AC:

1102

AN:

1461700

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

509

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.0138

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000427

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00361

AC:

550

AN:

152248

Hom.:

Cov.:

AF XY:

0.00347

AC XY:

258

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0118

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000689

Hom.:

Bravo

AF:

0.00391

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00128

AC:

155

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2020	This variant is associated with the following publications: (PMID: 29264398) -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2021

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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

6.1

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.55

D;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.53

T;T;T

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.3

M;.;M

MutationTaster

Benign

0.67

N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.4

N;D;N

REVEL

Uncertain

0.31

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.0030

B;.;.

Vest4

0.20

MutPred

0.78

Gain of methylation at N1044 (P = 0.0046);.;Gain of methylation at N1044 (P = 0.0046);

MVP

0.71

MPC

0.17

ClinPred

0.012

GERP RS

-2.3

Varity_R

0.13

gMVP

0.44

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