rs2273506

Positions:

chr20-63359587-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000744.7(CHRNA4):c.189C>T(p.Leu63=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0793 in 1,612,634 control chromosomes in the GnomAD database, including 5,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.096 ( 747 hom., cov: 34)

Exomes 𝑓: 0.078 ( 5178 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -3.33

Variant links:

Genes affected

CHRNA4 (HGNC:1958): (cholinergic receptor nicotinic alpha 4 subunit) This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

CHRNA4 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=-0.86).

BP6

Variant 20-63359587-G-A is Benign according to our data. Variant chr20-63359587-G-A is described in ClinVar as [Benign]. Clinvar id is 128747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63359587-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CHRNA4	NM_000744.7 linkuse as main transcript	c.189C>T	p.Leu63=	synonymous_variant	2/6	ENST00000370263.9
CHRNA4	NM_001256573.2 linkuse as main transcript	c.-358C>T		5_prime_UTR_variant	2/6
CHRNA4	NR_046317.2 linkuse as main transcript	n.373C>T		non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9 linkuse as main transcript	c.189C>T	p.Leu63=	synonymous_variant	2/6	1	NM_000744.7	P1	P43681-1

Frequencies

GnomAD3 genomes

AF:

0.0957

AC:

14561

AN:

152168

Hom.:

745

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0764

Gnomad ASJ

AF:

0.0884

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.0873

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.0712

Gnomad OTH

AF:

0.105

GnomAD3 exomes

AF:

0.0924

AC:

23078

AN:

249840

Hom.:

1264

AF XY:

0.0953

AC XY:

12924

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.0478

Gnomad ASJ exome

AF:

0.0963

Gnomad EAS exome

AF:

0.130

Gnomad SAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.0886

Gnomad NFE exome

AF:

0.0746

Gnomad OTH exome

AF:

0.0913

GnomAD4 exome

AF:

0.0776

AC:

113252

AN:

1460348

Hom.:

5178

Cov.:

AF XY:

0.0799

AC XY:

58052

AN XY:

726460

show subpopulations

Gnomad4 AFR exome

AF:

0.142

Gnomad4 AMR exome

AF:

0.0510

Gnomad4 ASJ exome

AF:

0.101

Gnomad4 EAS exome

AF:

0.122

Gnomad4 SAS exome

AF:

0.160

Gnomad4 FIN exome

AF:

0.0869

Gnomad4 NFE exome

AF:

0.0668

Gnomad4 OTH exome

AF:

0.0846

GnomAD4 genome

AF:

0.0958

AC:

14584

AN:

152286

Hom.:

747

Cov.:

AF XY:

0.0967

AC XY:

7199

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.133

Gnomad4 AMR

AF:

0.0764

Gnomad4 ASJ

AF:

0.0884

Gnomad4 EAS

AF:

0.128

Gnomad4 SAS

AF:

0.163

Gnomad4 FIN

AF:

0.0873

Gnomad4 NFE

AF:

0.0712

Gnomad4 OTH

AF:

0.103

Alfa

AF:

0.0803

Hom.:

580

Bravo

AF:

0.0942

Asia WGS

AF:

0.145

AC:

502

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 20. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2016

This alteration is classified as 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.13

DANN

Benign

0.93

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