rs121912244

Positions:

chr20-63350950-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PP3_StrongBP6BS1BS2

The ENST00000370263.9(CHRNA4):c.461C>T(p.Pro154Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000961 in 1,613,674 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P154P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

CHRNA4
ENST00000370263.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 9.78

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

BP6

Variant 20-63350950-G-A is Benign according to our data. Variant chr20-63350950-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 98325.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, not_provided=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000999 (146/1461600) while in subpopulation NFE AF= 0.000121 (134/1112002). AF 95% confidence interval is 0.000104. There are 1 homozygotes in gnomad4_exome. There are 76 alleles in male gnomad4_exome subpopulation. Median coverage is 40. This position pass quality control queck.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHRNA4	NM_000744.7 linkuse as main transcript	c.461C>T	p.Pro154Leu	missense_variant	5/6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2 linkuse as main transcript	c.-68C>T		5_prime_UTR_variant	5/6		NP_001243502.1
CHRNA4	NR_046317.2 linkuse as main transcript	n.670C>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.461C>T	p.Pro154Leu	missense_variant	5/6	1	NM_000744.7	ENSP00000359285	P1	P43681-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

250824

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000999

AC:

146

AN:

1461600

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21683344) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

- -

Tobacco use disorder

Other:1

not provided, no classification provided

literature only

Psychiatry Genetics Yale University

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.1

H;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-9.3

D;.

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.93

MVP

0.94

MPC

1.2

ClinPred

1.0

GERP RS

4.9

Varity_R

0.84

gMVP

0.88

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