20-63352404-C-T

Position:

• chr20-63352404-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000370263.9(CHRNA4):​c.384-1377G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 152,062 control chromosomes in the GnomAD database, including 47,862 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 0.78 (47862 hom., cov: 32)
• Consequence: CHRNA4 ENST00000370263.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290

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 -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 = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.384-1377G>A		intron_variant		ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-145-1377G>A		intron_variant			NP_001243502.1
CHRNA4	NR_046317.2	n.593-1377G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.384-1377G>A		intron_variant		1	NM_000744.7	ENSP00000359285	P1

Frequencies

GnomAD3 genomes AF: 0.778 AC: 118173 AN: 151944 Hom.: 47842 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.865

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.894

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.882

Gnomad OTH AF: 0.788

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

GnomAD4 genome AF: 0.778 AC: 118231 AN: 152062 Hom.: 47862 Cov.: 32 AF XY: 0.782 AC XY: 58134 AN XY: 74322

Gnomad4 AFR AF: 0.523

Gnomad4 AMR AF: 0.865

Gnomad4 ASJ AF: 0.836

Gnomad4 EAS AF: 0.870

Gnomad4 SAS AF: 0.787

Gnomad4 FIN AF: 0.894

Gnomad4 NFE AF: 0.882

Gnomad4 OTH AF: 0.791

Alfa AF: 0.865 Hom.: 42541

Bravo AF: 0.765

Asia WGS AF: 0.814 AC: 2833 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.76
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6011776; hg19: chr20-61983756;