20-63347872-G-A

Variant names:

• chr20-63347872-G-A
• rs3787138
• NM_000744.7:c.1759-1009C>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.1759-1009C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 152,162 control chromosomes in the GnomAD database, including 47,563 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 0.78 (47563 hom., cov: 33)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34
• Publications: 25 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 = 0.869 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000744.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	NM_000744.7	MANE Select	c.1759-1009C>T		intron	N/A	NP_000735.1
	CHRNA4	NM_001256573.2		c.1231-1009C>T		intron	N/A	NP_001243502.1
	CHRNA4	NR_046317.2		n.1968-1009C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.1759-1009C>T		intron	N/A	ENSP00000359285.4
	CHRNA4	ENST00000463705.5	TSL:1	n.2407-1009C>T		intron	N/A
	CHRNA4	ENST00000467563.3	TSL:1	n.1829-1009C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118135 AN: 152044 Hom.: 47544 Cov.: 33

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.828

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.783

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.779

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

GnomAD4 genome AF: 0.777 AC: 118200 AN: 152162 Hom.: 47563 Cov.: 33 AF XY: 0.782 AC XY: 58157 AN XY: 74406

African (AFR) AF: 0.541 AC: 22436 AN: 41490

American (AMR) AF: 0.855 AC: 13084 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 2874 AN: 3472

East Asian (EAS) AF: 0.869 AC: 4491 AN: 5168

South Asian (SAS) AF: 0.784 AC: 3779 AN: 4822

European-Finnish (FIN) AF: 0.879 AC: 9321 AN: 10600

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.875 AC: 59511 AN: 68000

Other (OTH) AF: 0.782 AC: 1649 AN: 2108

Alfa AF: 0.850 Hom.: 61157

Bravo AF: 0.765

Asia WGS AF: 0.816 AC: 2840 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.28
DANN	Benign	0.60
PhyloP100		-2.3
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: rs3787138; hg19: chr20-61979224; COSMIC: COSV64721263; COSMIC: COSV64721263;