rs55915440

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000744.7(CHRNA4):c.1352C>T(p.Pro451Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,512,448 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P451P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0028 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 17 hom. )

Consequence

CHRNA4
NM_000744.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.382

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 (MetaRNN=0.005767554).

BP6

Variant 20-63350059-G-A is Benign according to our data. Variant chr20-63350059-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63350059-G-A is described in Lovd as [Likely_benign]. Variant chr20-63350059-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00282 (429/152326) while in subpopulation SAS AF= 0.00828 (40/4828). AF 95% confidence interval is 0.00625. There are 3 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 429 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7 linkuse as main transcript	c.1352C>T	p.Pro451Leu	missense_variant	5/6	ENST00000370263.9	NP_000735.1	P43681-1B4DK78Q59FV0
CHRNA4	NM_001256573.2 linkuse as main transcript	c.824C>T	p.Pro275Leu	missense_variant	5/6		NP_001243502.1	P43681Q4VAQ3B4DK78Q59FV0
CHRNA4	NR_046317.2 linkuse as main transcript	n.1561C>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.1352C>T	p.Pro451Leu	missense_variant	5/6	1	NM_000744.7	ENSP00000359285.4		P43681-1

Frequencies

GnomAD3 genomes

AF:

0.00282

AC:

429

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00340

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00307

AC:

405

AN:

131754

Hom.:

AF XY:

0.00318

AC XY:

221

AN XY:

69600

show subpopulations

Gnomad AFR exome

AF:

0.000224

Gnomad AMR exome

AF:

0.000893

Gnomad ASJ exome

AF:

0.0177

Gnomad EAS exome

AF:

0.0000801

Gnomad SAS exome

AF:

0.00891

Gnomad FIN exome

AF:

0.000668

Gnomad NFE exome

AF:

0.00299

Gnomad OTH exome

AF:

0.00263

GnomAD4 exome

AF:

0.00372

AC:

5061

AN:

1360122

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

2582

AN XY:

665314

show subpopulations

Gnomad4 AFR exome

AF:

0.000322

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.0185

Gnomad4 EAS exome

AF:

0.0000539

Gnomad4 SAS exome

AF:

0.00960

Gnomad4 FIN exome

AF:

0.00104

Gnomad4 NFE exome

AF:

0.00342

Gnomad4 OTH exome

AF:

0.00439

GnomAD4 genome

AF:

0.00282

AC:

429

AN:

152326

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

191

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00829

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00338

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00508

Hom.:

Bravo

AF:

0.00261

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000239

AC:

ESP6500EA

AF:

0.00242

AC:

ExAC

AF:

0.00270

AC:

316

Asia WGS

AF:

0.00635

AC:

AN:

3478

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2012	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 13, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CHRNA4: BP4, BS2 -
Likely 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

Jan 30, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 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

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.51

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0058

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.14

Sift

Benign

0.21

T;.

Sift4G

Benign

0.14

T;T

Polyphen

0.0040

B;.

Vest4

0.15

MVP

0.74

MPC

0.41

ClinPred

0.0025

GERP RS

2.6

Varity_R

0.028

gMVP

0.27

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