20-63361115-C-T

Position:

chr20-63361115-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000370263.9(CHRNA4):c.51G>A(p.Leu17=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0777 in 1,477,178 control chromosomes in the GnomAD database, including 4,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.059 ( 355 hom., cov: 32)

Exomes 𝑓: 0.080 ( 4507 hom. )

Consequence

CHRNA4
ENST00000370263.9 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0920

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 20-63361115-C-T is Benign according to our data. Variant chr20-63361115-C-T is described in ClinVar as [Benign]. Clinvar id is 93430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63361115-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.092 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHRNA4	NM_000744.7 linkuse as main transcript	c.51G>A	p.Leu17=	synonymous_variant	1/6	ENST00000370263.9	NP_000735.1
LOC100130587	NR_110634.1 linkuse as main transcript	n.183-703C>T		intron_variant, non_coding_transcript_variant
CHRNA4	NM_001256573.2 linkuse as main transcript	c.-471+62G>A		intron_variant			NP_001243502.1
CHRNA4	NR_046317.2 linkuse as main transcript	n.235G>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 linkuse as main transcript	c.51G>A	p.Leu17=	synonymous_variant	1/6	1	NM_000744.7	ENSP00000359285	P1	P43681-1
	ENST00000370257.1 linkuse as main transcript	n.183-703C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0588

AC:

8925

AN:

151852

Hom.:

355

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0145

Gnomad AMI

AF:

0.0442

Gnomad AMR

AF:

0.0463

Gnomad ASJ

AF:

0.0986

Gnomad EAS

AF:

0.000394

Gnomad SAS

AF:

0.0332

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.0510

Gnomad NFE

AF:

0.0856

Gnomad OTH

AF:

0.0610

GnomAD3 exomes

AF:

0.0605

AC:

5163

AN:

85354

Hom.:

210

AF XY:

0.0615

AC XY:

2984

AN XY:

48522

show subpopulations

Gnomad AFR exome

AF:

0.00679

Gnomad AMR exome

AF:

0.0303

Gnomad ASJ exome

AF:

0.0789

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0433

Gnomad FIN exome

AF:

0.0973

Gnomad NFE exome

AF:

0.0873

Gnomad OTH exome

AF:

0.0601

GnomAD4 exome

AF:

0.0799

AC:

105881

AN:

1325218

Hom.:

4507

Cov.:

AF XY:

0.0794

AC XY:

51831

AN XY:

652696

show subpopulations

Gnomad4 AFR exome

AF:

0.0109

Gnomad4 AMR exome

AF:

0.0350

Gnomad4 ASJ exome

AF:

0.0851

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0428

Gnomad4 FIN exome

AF:

0.0972

Gnomad4 NFE exome

AF:

0.0877

Gnomad4 OTH exome

AF:

0.0700

GnomAD4 genome

AF:

0.0587

AC:

8920

AN:

151960

Hom.:

355

Cov.:

AF XY:

0.0581

AC XY:

4318

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0145

Gnomad4 AMR

AF:

0.0461

Gnomad4 ASJ

AF:

0.0986

Gnomad4 EAS

AF:

0.000395

Gnomad4 SAS

AF:

0.0332

Gnomad4 FIN

AF:

0.105

Gnomad4 NFE

AF:

0.0857

Gnomad4 OTH

AF:

0.0604

Alfa

AF:

0.0457

Hom.:

Bravo

AF:

0.0528

Asia WGS

AF:

0.0160

AC:

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 11, 2017

- -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 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

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.90

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