rs143103435

Positions:

chr20-63356062-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000370263.9(CHRNA4):c.296G>A(p.Arg99His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,593,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R99C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CHRNA4
ENST00000370263.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 1.98

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040449172).

BP6

Variant 20-63356062-C-T is Benign according to our data. Variant chr20-63356062-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205045.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, not_provided=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000179 (260/1454016) while in subpopulation MID AF= 0.000523 (3/5740). AF 95% confidence interval is 0.000142. There are 0 homozygotes in gnomad4_exome. There are 143 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHRNA4	NM_000744.7 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	4/6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2 linkuse as main transcript	c.-251G>A		5_prime_UTR_variant	4/6		NP_001243502.1
CHRNA4	NR_046317.2 linkuse as main transcript	n.505G>A		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	4/6	1	NM_000744.7	ENSP00000359285	P1	P43681-1

Frequencies

GnomAD3 genomes

AF:

0.000201

AC:

AN:

139248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000747

Gnomad ASJ

AF:

0.00684

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000613

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000326

AC:

AN:

248256

Hom.:

AF XY:

0.000400

AC XY:

AN XY:

134912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00642

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000807

Gnomad OTH exome

AF:

0.000987

GnomAD4 exome

AF:

0.000179

AC:

260

AN:

1454016

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

143

AN XY:

723242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00699

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000370

Gnomad4 OTH exome

AF:

0.000501

GnomAD4 genome

AF:

0.000201

AC:

AN:

139248

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

AN XY:

66850

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000747

Gnomad4 ASJ

AF:

0.00684

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000613

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000403

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000257

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2020	- -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2019

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. -

Autosomal dominant nocturnal frontal lobe epilepsy 1

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as Uncertain significance and reported on 06/02/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Benign

-0.031

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.040

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.46

Sift

Uncertain

0.021

Sift4G

Uncertain

0.032

Polyphen

0.17

Vest4

0.46

MVP

0.78

MPC

0.51

ClinPred

0.11

GERP RS

3.2

Varity_R

0.21

gMVP

0.53

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