rs2236196

Variant names:

• chr20-63346204-G-A
• rs2236196
• ENST00000463705.5:n.3066C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-63346204-G-A
• chr20-63346204-G-C

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.150
• Publications: 59 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.*534C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NR_046317.2	n.2627C>T		non_coding_transcript_exon_variant	Exon 6 of 6
CHRNA4	NM_001256573.2	c.*534C>T		3_prime_UTR_variant	Exon 6 of 6		NP_001243502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000463705.5	n.3066C>T		non_coding_transcript_exon_variant	Exon 5 of 5	1
CHRNA4	ENST00000370263.9	c.*534C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_000744.7	ENSP00000359285.4
CHRNA4	ENST00000631289.1	n.732C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

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

GnomAD2 exomes AF: 0.713 AC: 92972 AN: 130384 AF XY: 0.705

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 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

African (AFR) AF: 0.351 AC: 3002 AN: 8562

American (AMR) AF: 0.825 AC: 22489 AN: 27268

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 6380 AN: 10784

East Asian (EAS) AF: 0.862 AC: 7949 AN: 9218

South Asian (SAS) AF: 0.617 AC: 36794 AN: 59634

European-Finnish (FIN) AF: 0.728 AC: 9013 AN: 12378

Middle Eastern (MID) AF: 0.588 AC: 676 AN: 1150

European-Non Finnish (NFE) AF: 0.739 AC: 117353 AN: 158848

Other (OTH) AF: 0.687 AC: 9651 AN: 14056

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

African (AFR) AF: 0.366 AC: 15185 AN: 41504

American (AMR) AF: 0.729 AC: 11157 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2080 AN: 3470

East Asian (EAS) AF: 0.860 AC: 4429 AN: 5152

South Asian (SAS) AF: 0.600 AC: 2895 AN: 4828

European-Finnish (FIN) AF: 0.724 AC: 7672 AN: 10594

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.737 AC: 50076 AN: 67976

Other (OTH) AF: 0.631 AC: 1330 AN: 2108

Alfa AF: 0.696 Hom.: 83990

Bravo AF: 0.620

Asia WGS AF: 0.720 AC: 2504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.93
DANN	Benign	0.53
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2236196; hg19: chr20-61977556;