20-63358042-T-C

Variant names:

• chr20-63358042-T-C
• rs3787141
• NM_000744.7:c.228+1506A>G

Variant summary

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

The NM_000744.7(CHRNA4):​c.228+1506A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0984 in 152,140 control chromosomes in the GnomAD database, including 806 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 0.098 (806 hom., cov: 33)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.470
• Publications: 4 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 (SAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.228+1506A>G		intron_variant	Intron 2 of 5	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-319+1506A>G		intron_variant	Intron 2 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.412+1506A>G		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.228+1506A>G		intron_variant	Intron 2 of 5	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.0982 AC: 14936 AN: 152022 Hom.: 804 Cov.: 33

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0774

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0871

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0715

Gnomad OTH AF: 0.106

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

GnomAD4 genome AF: 0.0984 AC: 14966 AN: 152140 Hom.: 806 Cov.: 33 AF XY: 0.0994 AC XY: 7390 AN XY: 74376

African (AFR) AF: 0.141 AC: 5866 AN: 41496

American (AMR) AF: 0.0774 AC: 1184 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3468

East Asian (EAS) AF: 0.130 AC: 673 AN: 5160

South Asian (SAS) AF: 0.166 AC: 799 AN: 4826

European-Finnish (FIN) AF: 0.0871 AC: 922 AN: 10586

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0715 AC: 4863 AN: 67990

Other (OTH) AF: 0.104 AC: 220 AN: 2112

Alfa AF: 0.0306 Hom.: 23

Bravo AF: 0.0970

Asia WGS AF: 0.149 AC: 517 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	11
DANN	Benign	0.86
PhyloP100		-0.47
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: rs3787141; hg19: chr20-61989394;