20-63357759-T-C

Position:

• chr20-63357759-T-C

Variant summary

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

The NM_000744.7(CHRNA4):​c.229-1344A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0984 in 152,150 control chromosomes in the GnomAD database, including 806 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 0.098 (806 hom., cov: 33)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.99

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=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.229-1344A>G		intron_variant		ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-318-1344A>G		intron_variant			NP_001243502.1
CHRNA4	NR_046317.2	n.413-1344A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.229-1344A>G		intron_variant		1	NM_000744.7	ENSP00000359285	P1

Frequencies

GnomAD3 genomes AF: 0.0982 AC: 14936 AN: 152032 Hom.: 804 Cov.: 33

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0774

Gnomad ASJ AF: 0.0890

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0872

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0716

Gnomad OTH AF: 0.106

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

GnomAD4 genome AF: 0.0984 AC: 14966 AN: 152150 Hom.: 806 Cov.: 33 AF XY: 0.0994 AC XY: 7393 AN XY: 74380

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0775

Gnomad4 ASJ AF: 0.0890

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.0872

Gnomad4 NFE AF: 0.0716

Gnomad4 OTH AF: 0.104

Alfa AF: 0.0839 Hom.: 181

Bravo AF: 0.0970

Asia WGS AF: 0.149 AC: 516 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.53
DANN	Benign	0.78

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: rs3787140; hg19: chr20-61989111;