rs1044396

chr20-63349782-G-Achr20-63349782-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000744.7(CHRNA4):c.1629C>T(p.Ser543=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,609,060 control chromosomes in the GnomAD database, including 220,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (15024 hom., cov: 34)
  • Exomes 𝑓: 0.52 (205217 hom.)
• Consequence: CHRNA4 NM_000744.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.929

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-63349782-G-A is Benign according to our data. Variant chr20-63349782-G-A is described in ClinVar as [Benign]. Clinvar id is 93427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.929 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.1629C>T	p.Ser543=	synonymous_variant	5/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.1101C>T	p.Ser367=	synonymous_variant	5/6
CHRNA4	NR_046317.2	n.1838C>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1629C>T	p.Ser543=	synonymous_variant	5/6	1	NM_000744.7	P1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61427 AN: 152032 Hom.: 15016 Cov.: 34

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.413

GnomAD3 exomes AF: 0.471 AC: 116275 AN: 247118 Hom.: 29237 AF XY: 0.475 AC XY: 63808 AN XY: 134266

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.257

Gnomad SAS exome AF: 0.436

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.486

GnomAD4 exome AF: 0.523 AC: 761794 AN: 1456910 Hom.: 205217 Cov.: 77 AF XY: 0.521 AC XY: 376959 AN XY: 724028

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.526

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.529

Gnomad4 NFE exome AF: 0.555

Gnomad4 OTH exome AF: 0.488

GnomAD4 genome AF: 0.404 AC: 61447 AN: 152150 Hom.: 15024 Cov.: 34 AF XY: 0.408 AC XY: 30309 AN XY: 74374

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.498

Gnomad4 ASJ AF: 0.432

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.541

Gnomad4 OTH AF: 0.416

Alfa AF: 0.500 Hom.: 19738

Bravo AF: 0.388

Asia WGS AF: 0.348 AC: 1212 AN: 3478

EpiCase AF: 0.527

EpiControl AF: 0.521

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2016	- -
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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28877969) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -

Autosomal dominant nocturnal frontal lobe epilepsy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 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. -

Nicotine addiction, protection against Benign:1

protective, no assertion criteria provided

literature only

OMIM

Jul 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.51
DANN	Benign	0.61

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

Other links and lift over

dbSNP: rs1044396; hg19: chr20-61981134; COSMIC: COSV64718823; COSMIC: COSV64718823;