ENST00000463705.5:n.1031+11068C>T

Variant names:

• chr20-63362813-G-A
• rs755204
• ENST00000463705.5:n.1031+11068C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000463705.5(CHRNA4):​n.1031+11068C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0863 in 152,240 control chromosomes in the GnomAD database, including 563 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.086 (563 hom., cov: 33)
• Consequence: CHRNA4 ENST00000463705.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0760
• Publications: 6 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

ENSG00000203900 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000463705.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOC100130587	NR_110634.1		n.306+872G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000463705.5	TSL:1	n.1031+11068C>T		intron	N/A
	CHRNA4	ENST00000675470.1		c.-964-295C>T		intron	N/A	ENSP00000502096.1
	ENSG00000203900	ENST00000370257.1	TSL:2	n.306+872G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0863 AC: 13130 AN: 152122 Hom.: 564 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0756

Gnomad ASJ AF: 0.0908

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0892

Gnomad FIN AF: 0.0875

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.0687

Gnomad OTH AF: 0.0986

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0863 AC: 13138 AN: 152240 Hom.: 563 Cov.: 33 AF XY: 0.0871 AC XY: 6481 AN XY: 74430

African (AFR) AF: 0.111 AC: 4607 AN: 41538

American (AMR) AF: 0.0757 AC: 1158 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 315 AN: 3468

East Asian (EAS) AF: 0.139 AC: 720 AN: 5180

South Asian (SAS) AF: 0.0890 AC: 430 AN: 4830

European-Finnish (FIN) AF: 0.0875 AC: 928 AN: 10604

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0687 AC: 4674 AN: 67998

Other (OTH) AF: 0.0971 AC: 205 AN: 2112

Alfa AF: 0.0742 Hom.: 183

Bravo AF: 0.0861

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.1
DANN	Benign	0.84
PhyloP100		-0.076

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs755204; hg19: chr20-61994165;