rs2236196

chr20-63346204-G-Achr20-63346204-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000744.7(CHRNA4):c.*534C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 454,030 control chromosomes in the GnomAD database, including 109,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32183 hom., cov: 33)
  • Exomes 𝑓: 0.71 (76932 hom.)
• Consequence: CHRNA4 NM_000744.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.150

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 20-63346204-G-A is Benign according to our data. Variant chr20-63346204-G-A is described in ClinVar as [Benign]. Clinvar id is 1169560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.*534C>T		3_prime_UTR_variant	6/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.*534C>T		3_prime_UTR_variant	6/6
CHRNA4	NR_046317.2	n.2627C>T		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.*534C>T		3_prime_UTR_variant	6/6	1	NM_000744.7	P1
CHRNA4	ENST00000463705.5	n.3066C>T		non_coding_transcript_exon_variant	5/5	1
CHRNA4	ENST00000631289.1	n.732C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95517 AN: 152014 Hom.: 32173 Cov.: 33

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.729

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.860

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.737

Gnomad OTH AF: 0.626

GnomAD3 exomes AF: 0.713 AC: 92972 AN: 130384 Hom.: 34078 AF XY: 0.705 AC XY: 50135 AN XY: 71156

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.826

Gnomad ASJ exome AF: 0.594

Gnomad EAS exome AF: 0.860

Gnomad SAS exome AF: 0.616

Gnomad FIN exome AF: 0.733

Gnomad NFE exome AF: 0.734

Gnomad OTH exome AF: 0.696

GnomAD4 exome AF: 0.707 AC: 213307 AN: 301898 Hom.: 76932 Cov.: 0 AF XY: 0.699 AC XY: 120231 AN XY: 172048

Gnomad4 AFR exome AF: 0.351

Gnomad4 AMR exome AF: 0.825

Gnomad4 ASJ exome AF: 0.592

Gnomad4 EAS exome AF: 0.862

Gnomad4 SAS exome AF: 0.617

Gnomad4 FIN exome AF: 0.728

Gnomad4 NFE exome AF: 0.739

Gnomad4 OTH exome AF: 0.687

GnomAD4 genome AF: 0.628 AC: 95561 AN: 152132 Hom.: 32183 Cov.: 33 AF XY: 0.633 AC XY: 47038 AN XY: 74366

Gnomad4 AFR AF: 0.366

Gnomad4 AMR AF: 0.729

Gnomad4 ASJ AF: 0.599

Gnomad4 EAS AF: 0.860

Gnomad4 SAS AF: 0.600

Gnomad4 FIN AF: 0.724

Gnomad4 NFE AF: 0.737

Gnomad4 OTH AF: 0.631

Alfa AF: 0.705 Hom.: 24926

Bravo AF: 0.620

Asia WGS AF: 0.720 AC: 2504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Autosomal dominant nocturnal frontal lobe epilepsy 1;C1861063:Tobacco addiction, susceptibility to Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.93
Dann	Benign	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

Other links and lift over

dbSNP: rs2236196; hg19: chr20-61977556;