rs6011770

Positions:

• chr20-63346079-C-T

Variant summary

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

The NM_000744.7(CHRNA4):​c.*659G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 454,028 control chromosomes in the GnomAD database, including 789 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 0.066 (552 hom., cov: 33)
  • Exomes 𝑓: 0.031 (237 hom.)
• Consequence: CHRNA4 NM_000744.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0120

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.*659G>A		3_prime_UTR_variant	6/6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.*659G>A		3_prime_UTR_variant	6/6		NP_001243502.1
CHRNA4	NR_046317.2	n.2752G>A		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263	c.*659G>A		3_prime_UTR_variant	6/6	1	NM_000744.7	ENSP00000359285.4
CHRNA4	ENST00000463705.5	n.3191G>A		non_coding_transcript_exon_variant	5/5	1
CHRNA4	ENST00000631289.1	n.*17G>A		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.0657 AC: 9997 AN: 152140 Hom.: 552 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.0494

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0356

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0636

GnomAD3 exomes AF: 0.0341 AC: 4441 AN: 130424 Hom.: 143 AF XY: 0.0316 AC XY: 2252 AN XY: 71194

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0336

Gnomad ASJ exome AF: 0.0593

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00728

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0452

GnomAD4 exome AF: 0.0313 AC: 9433 AN: 301770 Hom.: 237 Cov.: 0 AF XY: 0.0286 AC XY: 4914 AN XY: 171986

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0336

Gnomad4 ASJ exome AF: 0.0585

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00808

Gnomad4 FIN exome AF: 0.0265

Gnomad4 NFE exome AF: 0.0324

Gnomad4 OTH exome AF: 0.0434

GnomAD4 genome AF: 0.0658 AC: 10013 AN: 152258 Hom.: 552 Cov.: 33 AF XY: 0.0646 AC XY: 4813 AN XY: 74450

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.0493

Gnomad4 ASJ AF: 0.0588

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0356

Gnomad4 NFE AF: 0.0330

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0483 Hom.: 155

Bravo AF: 0.0711

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.6
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs6011770; hg19: chr20-61977431;