rs1044396

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.Ser543Ser) 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 rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7 link	c.1629C>T	p.Ser543Ser	synonymous_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1	P43681-1B4DK78Q59FV0
CHRNA4	NM_001256573.2 link	c.1101C>T	p.Ser367Ser	synonymous_variant	Exon 5 of 6		NP_001243502.1	P43681Q4VAQ3B4DK78Q59FV0
CHRNA4	NR_046317.2 link	n.1838C>T		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 link	c.1629C>T	p.Ser543Ser	synonymous_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4		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

Apr 12, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28877969) -

Autosomal dominant nocturnal frontal lobe epilepsy 1

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 01, 2004

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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