rs1044393

Positions:

Variant summary

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

The ENST00000370263.9(CHRNA4):c.639T>C(p.Asp213=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.862 in 1,613,240 control chromosomes in the GnomAD database, including 604,517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 47932 hom., cov: 28)

Exomes 𝑓: 0.87 ( 556585 hom. )

Consequence

CHRNA4
ENST00000370263.9 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.395

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=-0.76).

BP6

Variant 20-63350772-A-G is Benign according to our data. Variant chr20-63350772-A-G is described in ClinVar as [Benign]. Clinvar id is 128749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63350772-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.395 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.875 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.639T>C	p.Asp213=	synonymous_variant	5/6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2 linkuse as main transcript	c.111T>C	p.Asp37=	synonymous_variant	5/6		NP_001243502.1
CHRNA4	NR_046317.2 linkuse as main transcript	n.848T>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.639T>C	p.Asp213=	synonymous_variant	5/6	1	NM_000744.7	ENSP00000359285	P1	P43681-1

Frequencies

GnomAD3 genomes

AF:

0.781

AC:

118258

AN:

151408

Hom.:

47914

Cov.:

show subpopulations

Gnomad AFR

AF:

0.539

Gnomad AMI

AF:

0.914

Gnomad AMR

AF:

0.861

Gnomad ASJ

AF:

0.836

Gnomad EAS

AF:

0.870

Gnomad SAS

AF:

0.785

Gnomad FIN

AF:

0.894

Gnomad MID

AF:

0.756

Gnomad NFE

AF:

0.881

Gnomad OTH

AF:

0.788

GnomAD3 exomes

AF:

0.846

AC:

212327

AN:

251030

Hom.:

90951

AF XY:

0.847

AC XY:

115041

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.527

Gnomad AMR exome

AF:

0.914

Gnomad ASJ exome

AF:

0.827

Gnomad EAS exome

AF:

0.868

Gnomad SAS exome

AF:

0.782

Gnomad FIN exome

AF:

0.889

Gnomad NFE exome

AF:

0.878

Gnomad OTH exome

AF:

0.847

GnomAD4 exome

AF:

0.870

AC:

1271958

AN:

1461714

Hom.:

556585

Cov.:

AF XY:

0.869

AC XY:

631585

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.519

Gnomad4 AMR exome

AF:

0.908

Gnomad4 ASJ exome

AF:

0.824

Gnomad4 EAS exome

AF:

0.877

Gnomad4 SAS exome

AF:

0.786

Gnomad4 FIN exome

AF:

0.889

Gnomad4 NFE exome

AF:

0.887

Gnomad4 OTH exome

AF:

0.852

GnomAD4 genome

AF:

0.781

AC:

118314

AN:

151526

Hom.:

47932

Cov.:

AF XY:

0.785

AC XY:

58109

AN XY:

73998

show subpopulations

Gnomad4 AFR

AF:

0.538

Gnomad4 AMR

AF:

0.861

Gnomad4 ASJ

AF:

0.836

Gnomad4 EAS

AF:

0.869

Gnomad4 SAS

AF:

0.786

Gnomad4 FIN

AF:

0.894

Gnomad4 NFE

AF:

0.881

Gnomad4 OTH

AF:

0.791

Alfa

AF:

0.825

Hom.:

19739

Bravo

AF:

0.769

Asia WGS

AF:

0.811

AC:

2821

AN:

3478

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	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. -
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 99% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 92. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -

not provided

Benign:3

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

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

-0.76

CADD

Benign

0.48

DANN

Benign

0.58

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