rs3827020

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000744.7(CHRNA4):c.1758+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,612,344 control chromosomes in the GnomAD database, including 32,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3203 hom., cov: 34)

Exomes 𝑓: 0.19 ( 29164 hom. )

Consequence

CHRNA4
NM_000744.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -7.11

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 20-63349639-T-C is Benign according to our data. Variant chr20-63349639-T-C is described in ClinVar as [Benign]. Clinvar id is 93429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63349639-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
CHRNA4	NM_000744.7 linkuse as main transcript	c.1758+14A>G	intron_variant	ENST00000370263.9	NP_000735.1	P43681-1B4DK78Q59FV0
CHRNA4	NM_001256573.2 linkuse as main transcript	c.1230+14A>G	intron_variant		NP_001243502.1	P43681Q4VAQ3B4DK78Q59FV0
CHRNA4	NR_046317.2 linkuse as main transcript	n.1967+14A>G	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 linkuse as main transcript	c.1758+14A>G		intron_variant		1	NM_000744.7	ENSP00000359285.4		P43681-1

Frequencies

GnomAD3 genomes

AF:

0.197

AC:

29983

AN:

152102

Hom.:

3202

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.297

Gnomad AMR

AF:

0.220

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.208

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.198

GnomAD3 exomes

AF:

0.217

AC:

53721

AN:

247432

Hom.:

6752

AF XY:

0.210

AC XY:

28250

AN XY:

134520

show subpopulations

Gnomad AFR exome

AF:

0.170

Gnomad AMR exome

AF:

0.299

Gnomad ASJ exome

AF:

0.147

Gnomad EAS exome

AF:

0.467

Gnomad SAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.199

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.194

GnomAD4 exome

AF:

0.192

AC:

280902

AN:

1460124

Hom.:

29164

Cov.:

AF XY:

0.192

AC XY:

139178

AN XY:

726396

show subpopulations

Gnomad4 AFR exome

AF:

0.174

Gnomad4 AMR exome

AF:

0.289

Gnomad4 ASJ exome

AF:

0.155

Gnomad4 EAS exome

AF:

0.463

Gnomad4 SAS exome

AF:

0.163

Gnomad4 FIN exome

AF:

0.200

Gnomad4 NFE exome

AF:

0.182

Gnomad4 OTH exome

AF:

0.194

GnomAD4 genome

AF:

0.197

AC:

29990

AN:

152220

Hom.:

3203

Cov.:

AF XY:

0.198

AC XY:

14734

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.176

Gnomad4 AMR

AF:

0.220

Gnomad4 ASJ

AF:

0.148

Gnomad4 EAS

AF:

0.474

Gnomad4 SAS

AF:

0.164

Gnomad4 FIN

AF:

0.208

Gnomad4 NFE

AF:

0.186

Gnomad4 OTH

AF:

0.200

Alfa

AF:

0.137

Hom.:

357

Bravo

AF:

0.201

Asia WGS

AF:

0.319

AC:

1107

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

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 38% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 35. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.052

DANN

Benign

0.26

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