rs80075498

Positions:

chr20-63361157-T-C

Variant summary

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

The NM_000744.7(CHRNA4):c.9A>G(p.Leu3Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,479,910 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0037 ( 11 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.645

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 20-63361157-T-C is Benign according to our data. Variant chr20-63361157-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 136767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63361157-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.645 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00266 (403/151336) while in subpopulation SAS AF= 0.00479 (23/4800). AF 95% confidence interval is 0.00327. There are 2 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 403 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7 linkuse as main transcript	c.9A>G	p.Leu3Leu	synonymous_variant	1/6	ENST00000370263.9	NP_000735.1	P43681-1B4DK78Q59FV0
CHRNA4	NM_001256573.2 linkuse as main transcript	c.-471+20A>G		intron_variant			NP_001243502.1	P43681Q4VAQ3B4DK78Q59FV0
CHRNA4	NR_046317.2 linkuse as main transcript	n.193A>G		non_coding_transcript_exon_variant	1/6
LOC100130587	NR_110634.1 linkuse as main transcript	n.183-661T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 linkuse as main transcript	c.9A>G	p.Leu3Leu	synonymous_variant	1/6	1	NM_000744.7	ENSP00000359285.4		P43681-1

Frequencies

GnomAD3 genomes

AF:

0.00267

AC:

404

AN:

151226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.0226

Gnomad EAS

AF:

0.000401

Gnomad SAS

AF:

0.00479

Gnomad FIN

AF:

0.000476

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00331

Gnomad OTH

AF:

0.00578

GnomAD3 exomes

AF:

0.00417

AC:

356

AN:

85474

Hom.:

AF XY:

0.00454

AC XY:

220

AN XY:

48470

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000806

Gnomad ASJ exome

AF:

0.0187

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00608

Gnomad FIN exome

AF:

0.000205

Gnomad NFE exome

AF:

0.00318

Gnomad OTH exome

AF:

0.00433

GnomAD4 exome

AF:

0.00368

AC:

4884

AN:

1328574

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

2483

AN XY:

654314

show subpopulations

Gnomad4 AFR exome

AF:

0.000223

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.0183

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00666

Gnomad4 FIN exome

AF:

0.00116

Gnomad4 NFE exome

AF:

0.00344

Gnomad4 OTH exome

AF:

0.00441

GnomAD4 genome

AF:

0.00266

AC:

403

AN:

151336

Hom.:

Cov.:

AF XY:

0.00237

AC XY:

175

AN XY:

73942

show subpopulations

Gnomad4 AFR

AF:

0.000484

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.0226

Gnomad4 EAS

AF:

0.000403

Gnomad4 SAS

AF:

0.00479

Gnomad4 FIN

AF:

0.000476

Gnomad4 NFE

AF:

0.00329

Gnomad4 OTH

AF:

0.00572

Alfa

AF:

0.00502

Hom.:

Bravo

AF:

0.00253

Asia WGS

AF:

0.00174

AC:

AN:

3466

ClinVar

Significance: Benign/Likely 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	Athena Diagnostics	Mar 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2015	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CHRNA4: BP4, BP7 -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2016

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. -

Autosomal dominant nocturnal frontal lobe epilepsy 1;C1861063:Tobacco addiction, susceptibility to

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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