rs4809549

Positions:

• chr20-63370757-G-C
• chr20-63370757-G-T

Variant summary

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

The ENST00000475033.5(CHRNA4):​n.3656C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 151,876 control chromosomes in the GnomAD database, including 15,926 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 0.45 (15924 hom., cov: 31)
  • Exomes 𝑓: 0.40 (2 hom.)
• Consequence: CHRNA4 ENST00000475033.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.126

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]

ENSG00000203900 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOC100130587	NR_110634.1	n.2948-104G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000463705.5	n.1031+3124C>G		intron_variant		1
CHRNA4	ENST00000475033.5	n.3656C>G		non_coding_transcript_exon_variant	4/4	2
ENSG00000203900	ENST00000370257.1	n.2948-104G>C		intron_variant		2
ENSG00000203900	ENST00000428531.1	n.325+185G>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68760 AN: 151738 Hom.: 15924 Cov.: 31

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.481

Gnomad OTH AF: 0.459

GnomAD4 exome AF: 0.400 AC: 8 AN: 20 Hom.: 2 Cov.: 0 AF XY: 0.400 AC XY: 4 AN XY: 10

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.417

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.453 AC: 68773 AN: 151856 Hom.: 15924 Cov.: 31 AF XY: 0.451 AC XY: 33484 AN XY: 74198

Gnomad4 AFR AF: 0.387

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.620

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.481

Gnomad4 OTH AF: 0.455

Alfa AF: 0.346 Hom.: 920

Bravo AF: 0.457

Asia WGS AF: 0.435 AC: 1512 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.74

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4809549; hg19: chr20-62002109; COSMIC: COSV64718181;