rs6011770

Variant names:

• chr20-63346079-C-T
• rs6011770
• ENST00000463705.5:n.3191G>A

Variant summary

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

The ENST00000463705.5(CHRNA4):​n.3191G>A 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 0.0428 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 ENST00000463705.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0120
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.*659G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NR_046317.2	n.2752G>A		non_coding_transcript_exon_variant	Exon 6 of 6
CHRNA4	NM_001256573.2	c.*659G>A		3_prime_UTR_variant	Exon 6 of 6		NP_001243502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000463705.5	n.3191G>A		non_coding_transcript_exon_variant	Exon 5 of 5	1
CHRNA4	ENST00000370263.9	c.*659G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_000744.7	ENSP00000359285.4
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

GnomAD2 exomes AF: 0.0341 AC: 4441 AN: 130424 AF XY: 0.0316

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 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

African (AFR) AF: 0.146 AC: 1250 AN: 8554

American (AMR) AF: 0.0336 AC: 917 AN: 27272

Ashkenazi Jewish (ASJ) AF: 0.0585 AC: 631 AN: 10786

East Asian (EAS) AF: 0.00 AC: 0 AN: 9210

South Asian (SAS) AF: 0.00808 AC: 482 AN: 59648

European-Finnish (FIN) AF: 0.0265 AC: 328 AN: 12366

Middle Eastern (MID) AF: 0.0652 AC: 75 AN: 1150

European-Non Finnish (NFE) AF: 0.0324 AC: 5141 AN: 158742

Other (OTH) AF: 0.0434 AC: 609 AN: 14042

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

African (AFR) AF: 0.146 AC: 6084 AN: 41558

American (AMR) AF: 0.0493 AC: 755 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 204 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4828

European-Finnish (FIN) AF: 0.0356 AC: 378 AN: 10618

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0330 AC: 2242 AN: 67996

Other (OTH) AF: 0.0629 AC: 133 AN: 2114

Alfa AF: 0.0497 Hom.: 210

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
PhyloP100		-0.012
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6011770; hg19: chr20-61977431;