20-63362590-A-G

Variant names:

• chr20-63362590-A-G
• rs2093107
• ENST00000463705.5:n.1031+11291T>C

Variant summary

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

The ENST00000463705.5(CHRNA4):​n.1031+11291T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 152,094 control chromosomes in the GnomAD database, including 53,163 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 0.82 (53163 hom., cov: 32)
• Consequence: CHRNA4 ENST00000463705.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.504
• Publications: 12 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.925 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+649A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000463705.5	TSL:1	n.1031+11291T>C		intron	N/A
	CHRNA4	ENST00000675470.1		c.-964-72T>C		intron	N/A	ENSP00000502096.1
	ENSG00000203900	ENST00000370257.1	TSL:2	n.306+649A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.823 AC: 125123 AN: 151976 Hom.: 53133 Cov.: 32

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.830

Gnomad AMR AF: 0.873

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.911

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.911

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.834

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

GnomAD4 genome AF: 0.823 AC: 125209 AN: 152094 Hom.: 53163 Cov.: 32 AF XY: 0.826 AC XY: 61417 AN XY: 74354

African (AFR) AF: 0.613 AC: 25414 AN: 41434

American (AMR) AF: 0.873 AC: 13340 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 3207 AN: 3470

East Asian (EAS) AF: 0.565 AC: 2903 AN: 5142

South Asian (SAS) AF: 0.912 AC: 4401 AN: 4828

European-Finnish (FIN) AF: 0.927 AC: 9837 AN: 10612

Middle Eastern (MID) AF: 0.908 AC: 265 AN: 292

European-Non Finnish (NFE) AF: 0.931 AC: 63320 AN: 68008

Other (OTH) AF: 0.836 AC: 1765 AN: 2112

Alfa AF: 0.892 Hom.: 228877

Bravo AF: 0.803

Asia WGS AF: 0.749 AC: 2608 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.9
DANN	Benign	0.27
PhyloP100		-0.50

Splicing

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

Other links and lift over

dbSNP: rs2093107; hg19: chr20-61993942;