20-63349752-C-T

Variant names:

• chr20-63349752-C-T
• rs1044397
• NM_000744.7:c.1659G>A

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.1659G>A​(p.Ala553Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,611,664 control chromosomes in the GnomAD database, including 222,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (15300 hom., cov: 34)
  • Exomes 𝑓: 0.53 (207278 hom.)
• Consequence: CHRNA4 NM_000744.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.63

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=-0.86).
• BP6: Variant 20-63349752-C-T is Benign according to our data. Variant chr20-63349752-C-T is described in ClinVar as [Benign]. Clinvar id is 93428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1659G>A	p.Ala553Ala	synonymous_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.1131G>A	p.Ala377Ala	synonymous_variant	Exon 5 of 6		NP_001243502.1
CHRNA4	NR_046317.2	n.1868G>A		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1659G>A	p.Ala553Ala	synonymous_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62297 AN: 152040 Hom.: 15290 Cov.: 34

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.417

GnomAD3 exomes AF: 0.482 AC: 119354 AN: 247732 Hom.: 30274 AF XY: 0.485 AC XY: 65372 AN XY: 134676

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.530

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.390

Gnomad SAS exome AF: 0.439

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.527 AC: 768498 AN: 1459506 Hom.: 207278 Cov.: 72 AF XY: 0.524 AC XY: 380500 AN XY: 725962

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.527

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.441

Gnomad4 FIN exome AF: 0.531

Gnomad4 NFE exome AF: 0.555

Gnomad4 OTH exome AF: 0.497

GnomAD4 genome AF: 0.410 AC: 62316 AN: 152158 Hom.: 15300 Cov.: 34 AF XY: 0.414 AC XY: 30808 AN XY: 74392

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.432

Gnomad4 EAS AF: 0.380

Gnomad4 SAS AF: 0.429

Gnomad4 FIN AF: 0.527

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.422

Alfa AF: 0.496 Hom.: 11472

Bravo AF: 0.394

Asia WGS AF: 0.393 AC: 1370 AN: 3478

EpiCase AF: 0.527

EpiControl AF: 0.520

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Apr 12, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 75% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 70. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy 1 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 01, 2004

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.057
DANN	Benign	0.58

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: rs1044397; hg19: chr20-61981104; COSMIC: COSV64719459; COSMIC: COSV64719459;