chr20-63349782-G-A

Position:

chr20-63349782-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.1629C>T(p.Ser543=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,609,060 control chromosomes in the GnomAD database, including 220,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 15024 hom., cov: 34)

Exomes 𝑓: 0.52 ( 205217 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.929

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 20-63349782-G-A is Benign according to our data. Variant chr20-63349782-G-A is described in ClinVar as [Benign]. Clinvar id is 93427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.929 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHRNA4	NM_000744.7 linkuse as main transcript	c.1629C>T	p.Ser543=	synonymous_variant	5/6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2 linkuse as main transcript	c.1101C>T	p.Ser367=	synonymous_variant	5/6		NP_001243502.1
CHRNA4	NR_046317.2 linkuse as main transcript	n.1838C>T		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.1629C>T	p.Ser543=	synonymous_variant	5/6	1	NM_000744.7	ENSP00000359285	P1	P43681-1

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61427

AN:

152032

Hom.:

15016

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.379

Gnomad AMR

AF:

0.498

Gnomad ASJ

AF:

0.432

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.524

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.541

Gnomad OTH

AF:

0.413

GnomAD3 exomes

AF:

0.471

AC:

116275

AN:

247118

Hom.:

29237

AF XY:

0.475

AC XY:

63808

AN XY:

134266

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.528

Gnomad ASJ exome

AF:

0.431

Gnomad EAS exome

AF:

0.257

Gnomad SAS exome

AF:

0.436

Gnomad FIN exome

AF:

0.530

Gnomad NFE exome

AF:

0.539

Gnomad OTH exome

AF:

0.486

GnomAD4 exome

AF:

0.523

AC:

761794

AN:

1456910

Hom.:

205217

Cov.:

AF XY:

0.521

AC XY:

376959

AN XY:

724028

show subpopulations

Gnomad4 AFR exome

AF:

0.108

Gnomad4 AMR exome

AF:

0.526

Gnomad4 ASJ exome

AF:

0.424

Gnomad4 EAS exome

AF:

0.272

Gnomad4 SAS exome

AF:

0.438

Gnomad4 FIN exome

AF:

0.529

Gnomad4 NFE exome

AF:

0.555

Gnomad4 OTH exome

AF:

0.488

GnomAD4 genome

AF:

0.404

AC:

61447

AN:

152150

Hom.:

15024

Cov.:

AF XY:

0.408

AC XY:

30309

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.128

Gnomad4 AMR

AF:

0.498

Gnomad4 ASJ

AF:

0.432

Gnomad4 EAS

AF:

0.253

Gnomad4 SAS

AF:

0.426

Gnomad4 FIN

AF:

0.524

Gnomad4 NFE

AF:

0.541

Gnomad4 OTH

AF:

0.416

Alfa

AF:

0.500

Hom.:

19738

Bravo

AF:

0.388

Asia WGS

AF:

0.348

AC:

1212

AN:

3478

EpiCase

AF:

0.527

EpiControl

AF:

0.521

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 74% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 69. Only high quality variants are reported. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28877969) -
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. -

Nicotine addiction, protection against

Benign:1

protective, no assertion criteria provided

literature only

OMIM

Jul 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.51

DANN

Benign

0.61

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