20-63348441-G-A

Variant names:

• chr20-63348441-G-A
• rs6062899
• NM_000744.7:c.1758+1212C>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.1758+1212C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.723 in 152,134 control chromosomes in the GnomAD database, including 41,432 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 0.72 (41432 hom., cov: 34)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1758+1212C>T		intron_variant	Intron 5 of 5	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.1230+1212C>T		intron_variant	Intron 5 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.1967+1212C>T		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1758+1212C>T		intron_variant	Intron 5 of 5	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.724 AC: 110006 AN: 152016 Hom.: 41417 Cov.: 34

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.880

Gnomad AMR AF: 0.821

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.825

Gnomad OTH AF: 0.733

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

GnomAD4 genome AF: 0.723 AC: 110064 AN: 152134 Hom.: 41432 Cov.: 34 AF XY: 0.725 AC XY: 53922 AN XY: 74366

African (AFR) AF: 0.492 AC: 20399 AN: 41478

American (AMR) AF: 0.821 AC: 12551 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 2684 AN: 3472

East Asian (EAS) AF: 0.861 AC: 4455 AN: 5174

South Asian (SAS) AF: 0.651 AC: 3135 AN: 4818

European-Finnish (FIN) AF: 0.772 AC: 8165 AN: 10580

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.825 AC: 56110 AN: 68006

Other (OTH) AF: 0.736 AC: 1554 AN: 2110

Alfa AF: 0.707 Hom.: 2349

Bravo AF: 0.720

Asia WGS AF: 0.750 AC: 2607 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.8
DANN	Benign	0.71
PhyloP100		1.2
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: rs6062899; hg19: chr20-61979793;