chr20-63349963-C-T

Position:

chr20-63349963-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_000744.7(CHRNA4):c.1448G>A(p.Arg483Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000195 in 1,562,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R483W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

CHRNA4
NM_000744.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.31

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000145 (22/152192) while in subpopulation NFE AF= 0.000294 (20/68028). AF 95% confidence interval is 0.000194. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CHRNA4	NM_000744.7 linkuse as main transcript	c.1448G>A	p.Arg483Gln	missense_variant	5/6	ENST00000370263.9
CHRNA4	NM_001256573.2 linkuse as main transcript	c.920G>A	p.Arg307Gln	missense_variant	5/6
CHRNA4	NR_046317.2 linkuse as main transcript	n.1657G>A		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9 linkuse as main transcript	c.1448G>A	p.Arg483Gln	missense_variant	5/6	1	NM_000744.7	P1	P43681-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000113

AC:

AN:

176754

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

95940

show subpopulations

Gnomad AFR exome

AF:

0.000101

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000147

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.000217

GnomAD4 exome

AF:

0.000200

AC:

282

AN:

1410694

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

131

AN XY:

696276

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000106

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000232

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000145

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000587

AC:

ExAC

AF:

0.0000846

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2016

The R483Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R483Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, this amino acid substitution is not predicted to occur within the transmembrane region of the protein, where the vast majority of pathogenic missense variants have been identified in association with epilepsy (Steinlein et al., 2010). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Autosomal dominant nocturnal frontal lobe epilepsy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Center for Precision Medicine, Vanderbilt University Medical Center

Mar 16, 2018

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 20, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

- -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.69

N;.

REVEL

Uncertain

0.50

Sift

Uncertain

0.025

D;.

Sift4G

Benign

0.29

T;T

Polyphen

1.0

D;.

Vest4

0.61

MVP

0.84

MPC

1.3

ClinPred

0.22

GERP RS

4.9

Varity_R

0.21

gMVP

0.39

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