20-63352404-C-T

Variant names:

• chr20-63352404-C-T
• rs6011776
• NM_000744.7:c.384-1377G>A

Variant summary

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

The NM_000744.7(CHRNA4):​c.384-1377G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 152,062 control chromosomes in the GnomAD database, including 47,862 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 (47862 hom., cov: 32)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290
• Publications: 9 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.876 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	NM_000744.7	MANE Select	c.384-1377G>A		intron	N/A	NP_000735.1	P43681-1
	CHRNA4	NM_001256573.2		c.-145-1377G>A		intron	N/A	NP_001243502.1	Q4VAQ3
	CHRNA4	NR_046317.2		n.593-1377G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.384-1377G>A		intron	N/A	ENSP00000359285.4	P43681-1
	CHRNA4	ENST00000463705.5	TSL:1	n.1032-1377G>A		intron	N/A
	CHRNA4	ENST00000467563.3	TSL:1	n.454-1377G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.778 AC: 118173 AN: 151944 Hom.: 47842 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.865

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.894

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.882

Gnomad OTH AF: 0.788

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

GnomAD4 genome AF: 0.778 AC: 118231 AN: 152062 Hom.: 47862 Cov.: 32 AF XY: 0.782 AC XY: 58134 AN XY: 74322

African (AFR) AF: 0.523 AC: 21649 AN: 41412

American (AMR) AF: 0.865 AC: 13230 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.836 AC: 2900 AN: 3470

East Asian (EAS) AF: 0.870 AC: 4488 AN: 5158

South Asian (SAS) AF: 0.787 AC: 3791 AN: 4814

European-Finnish (FIN) AF: 0.894 AC: 9476 AN: 10604

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

European-Non Finnish (NFE) AF: 0.882 AC: 59976 AN: 67994

Other (OTH) AF: 0.791 AC: 1670 AN: 2112

Alfa AF: 0.849 Hom.: 67500

Bravo AF: 0.765

Asia WGS AF: 0.814 AC: 2833 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.76
DANN	Benign	0.50
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6011776; hg19: chr20-61983756;