rs45442394

Variant names:

• chr20-63349642-G-A
• rs45442394
• NM_000744.7:c.1758+11C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000744.7(CHRNA4):​c.1758+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0559 in 1,612,614 control chromosomes in the GnomAD database, including 2,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (193 hom., cov: 34)
  • Exomes 𝑓: 0.057 (2606 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.14
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-63349642-G-A is Benign according to our data. Variant chr20-63349642-G-A is described in ClinVar as Benign. ClinVar VariationId is 136762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1758+11C>T		intron_variant	Intron 5 of 5	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.1230+11C>T		intron_variant	Intron 5 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.1967+11C>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+11C>T		intron_variant	Intron 5 of 5	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6536 AN: 152250 Hom.: 193 Cov.: 34

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0547

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0602

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0663

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0458 AC: 11326 AN: 247550 AF XY: 0.0477

Gnomad AFR exome AF: 0.00965

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0594

Gnomad NFE exome AF: 0.0660

Gnomad OTH exome AF: 0.0514

GnomAD4 exome AF: 0.0573 AC: 83617 AN: 1460246 Hom.: 2606 Cov.: 34 AF XY: 0.0571 AC XY: 41491 AN XY: 726464

African (AFR) AF: 0.00881 AC: 295 AN: 33468

American (AMR) AF: 0.0212 AC: 947 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0566 AC: 1478 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0331 AC: 2852 AN: 86256

European-Finnish (FIN) AF: 0.0602 AC: 3132 AN: 52054

Middle Eastern (MID) AF: 0.0451 AC: 260 AN: 5766

European-Non Finnish (NFE) AF: 0.0643 AC: 71528 AN: 1111808

Other (OTH) AF: 0.0518 AC: 3124 AN: 60360

GnomAD4 genome AF: 0.0429 AC: 6537 AN: 152368 Hom.: 193 Cov.: 34 AF XY: 0.0423 AC XY: 3152 AN XY: 74508

African (AFR) AF: 0.0112 AC: 464 AN: 41594

American (AMR) AF: 0.0287 AC: 439 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0547 AC: 190 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0277 AC: 134 AN: 4830

European-Finnish (FIN) AF: 0.0602 AC: 640 AN: 10630

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0663 AC: 4511 AN: 68022

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0606 Hom.: 108

Bravo AF: 0.0387

Asia WGS AF: 0.0110 AC: 40 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 08, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.3
DANN	Benign	0.50
PhyloP100		-3.1
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: rs45442394; hg19: chr20-61980994;