ENST00000463705.5:n.1031+10969C>T

Variant names:

• chr20-63362912-G-A
• rs755203
• ENST00000463705.5:n.1031+10969C>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+10969C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 152,022 control chromosomes in the GnomAD database, including 16,048 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 0.42 (16048 hom., cov: 33)
• Consequence: CHRNA4 ENST00000463705.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 23 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.551 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+971G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000463705.5	TSL:1	n.1031+10969C>T		intron	N/A
	CHRNA4	ENST00000675470.1		c.-964-394C>T		intron	N/A	ENSP00000502096.1
	ENSG00000203900	ENST00000370257.1	TSL:2	n.306+971G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63601 AN: 151904 Hom.: 16036 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.420

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

GnomAD4 genome AF: 0.418 AC: 63615 AN: 152022 Hom.: 16048 Cov.: 33 AF XY: 0.422 AC XY: 31370 AN XY: 74312

African (AFR) AF: 0.127 AC: 5279 AN: 41488

American (AMR) AF: 0.506 AC: 7726 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1736 AN: 3472

East Asian (EAS) AF: 0.391 AC: 2018 AN: 5158

South Asian (SAS) AF: 0.429 AC: 2064 AN: 4814

European-Finnish (FIN) AF: 0.539 AC: 5699 AN: 10570

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37726 AN: 67926

Other (OTH) AF: 0.424 AC: 893 AN: 2108

Alfa AF: 0.494 Hom.: 48623

Bravo AF: 0.401

Asia WGS AF: 0.407 AC: 1416 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.52
DANN	Benign	0.35
PhyloP100		-1.3

Splicing

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

Other links and lift over

dbSNP: rs755203; hg19: chr20-61994264;