chr20-63350733-A-G

Position:

chr20-63350733-A-G

Variant summary

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

The NM_000744.7(CHRNA4):c.678T>C(p.Cys226Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,604,470 control chromosomes in the GnomAD database, including 666,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 49090 hom., cov: 27)

Exomes 𝑓: 0.92 ( 617802 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.186

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:

CHRNA4 (HGNC:):

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=-0.73).

BP6

Variant 20-63350733-A-G is Benign according to our data. Variant chr20-63350733-A-G is described in ClinVar as [Benign]. Clinvar id is 128750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63350733-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.186 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7 linkuse as main transcript	c.678T>C	p.Cys226Cys	synonymous_variant	5/6	ENST00000370263.9	NP_000735.1	P43681-1B4DK78Q59FV0
CHRNA4	NM_001256573.2 linkuse as main transcript	c.150T>C	p.Cys50Cys	synonymous_variant	5/6		NP_001243502.1	P43681Q4VAQ3B4DK78Q59FV0
CHRNA4	NR_046317.2 linkuse as main transcript	n.887T>C		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 linkuse as main transcript	c.678T>C	p.Cys226Cys	synonymous_variant	5/6	1	NM_000744.7	ENSP00000359285.4		P43681-1

Frequencies

GnomAD3 genomes

AF:

0.829

AC:

118747

AN:

143160

Hom.:

49067

Cov.:

show subpopulations

Gnomad AFR

AF:

0.646

Gnomad AMI

AF:

0.962

Gnomad AMR

AF:

0.886

Gnomad ASJ

AF:

0.840

Gnomad EAS

AF:

0.952

Gnomad SAS

AF:

0.922

Gnomad FIN

AF:

0.932

Gnomad MID

AF:

0.836

Gnomad NFE

AF:

0.893

Gnomad OTH

AF:

0.840

GnomAD3 exomes

AF:

0.923

AC:

231165

AN:

250536

Hom.:

107371

AF XY:

0.927

AC XY:

125753

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.644

Gnomad AMR exome

AF:

0.952

Gnomad ASJ exome

AF:

0.893

Gnomad EAS exome

AF:

0.982

Gnomad SAS exome

AF:

0.948

Gnomad FIN exome

AF:

0.943

Gnomad NFE exome

AF:

0.936

Gnomad OTH exome

AF:

0.923

GnomAD4 exome

AF:

0.920

AC:

1343602

AN:

1461194

Hom.:

617802

Cov.:

AF XY:

0.920

AC XY:

668587

AN XY:

726880

show subpopulations

Gnomad4 AFR exome

AF:

0.632

Gnomad4 AMR exome

AF:

0.916

Gnomad4 ASJ exome

AF:

0.878

Gnomad4 EAS exome

AF:

0.938

Gnomad4 SAS exome

AF:

0.909

Gnomad4 FIN exome

AF:

0.933

Gnomad4 NFE exome

AF:

0.929

Gnomad4 OTH exome

AF:

0.908

GnomAD4 genome

AF:

0.829

AC:

118826

AN:

143276

Hom.:

49090

Cov.:

AF XY:

0.839

AC XY:

59010

AN XY:

70344

show subpopulations

Gnomad4 AFR

AF:

0.646

Gnomad4 AMR

AF:

0.886

Gnomad4 ASJ

AF:

0.840

Gnomad4 EAS

AF:

0.952

Gnomad4 SAS

AF:

0.922

Gnomad4 FIN

AF:

0.932

Gnomad4 NFE

AF:

0.893

Gnomad4 OTH

AF:

0.841

Alfa

AF:

0.917

Hom.:

81422

Bravo

AF:

0.849

Asia WGS

AF:

0.915

AC:

3181

AN:

3478

EpiCase

AF:

0.935

EpiControl

AF:

0.929

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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 100% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 93. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal dominant nocturnal frontal lobe epilepsy 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.10

DANN

Benign

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