rs4522666

Variant names:

• chr20-63343128-G-A
• rs4522666
• NM_000744.7:c.*3610C>T

Variant summary

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

The NM_000744.7(CHRNA4):​c.*3610C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 350,944 control chromosomes in the GnomAD database, including 57,229 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 0.48 (21094 hom., cov: 33)
  • Exomes 𝑓: 0.59 (36135 hom.)
• Consequence: CHRNA4 NM_000744.7 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0170
• Publications: 16 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.*3610C>T		downstream_gene_variant		ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.*3610C>T		downstream_gene_variant			NP_001243502.1
CHRNA4	NR_046317.2	n.*95C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.*3610C>T		downstream_gene_variant		1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73240 AN: 152032 Hom.: 21085 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.505

GnomAD4 exome AF: 0.595 AC: 118210 AN: 198794 Hom.: 36135 AF XY: 0.591 AC XY: 64158 AN XY: 108606

African (AFR) AF: 0.136 AC: 705 AN: 5168

American (AMR) AF: 0.573 AC: 6424 AN: 11206

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2608 AN: 4484

East Asian (EAS) AF: 0.445 AC: 3655 AN: 8206

South Asian (SAS) AF: 0.561 AC: 23452 AN: 41832

European-Finnish (FIN) AF: 0.622 AC: 5432 AN: 8738

Middle Eastern (MID) AF: 0.544 AC: 361 AN: 664

European-Non Finnish (NFE) AF: 0.642 AC: 69928 AN: 108966

Other (OTH) AF: 0.592 AC: 5645 AN: 9530

GnomAD4 genome AF: 0.481 AC: 73260 AN: 152150 Hom.: 21094 Cov.: 33 AF XY: 0.486 AC XY: 36121 AN XY: 74378

African (AFR) AF: 0.148 AC: 6135 AN: 41534

American (AMR) AF: 0.558 AC: 8530 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 1998 AN: 3472

East Asian (EAS) AF: 0.442 AC: 2283 AN: 5160

South Asian (SAS) AF: 0.537 AC: 2593 AN: 4826

European-Finnish (FIN) AF: 0.637 AC: 6737 AN: 10582

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.637 AC: 43282 AN: 67980

Other (OTH) AF: 0.506 AC: 1067 AN: 2108

Alfa AF: 0.588 Hom.: 42322

Bravo AF: 0.460

Asia WGS AF: 0.470 AC: 1638 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.4
DANN	Benign	0.61
PhyloP100		0.017

Splicing

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

Other links and lift over

dbSNP: rs4522666; hg19: chr20-61974480;