rs45442394

Positions:

• chr20-63349642-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 136762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63349642-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1758+11C>T		intron_variant		ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.1230+11C>T		intron_variant			NP_001243502.1
CHRNA4	NR_046317.2	n.1967+11C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1758+11C>T		intron_variant		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

GnomAD3 exomes AF: 0.0458 AC: 11326 AN: 247550 Hom.: 347 AF XY: 0.0477 AC XY: 6421 AN XY: 134574

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 SAS exome AF: 0.0329

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

Gnomad4 AFR exome AF: 0.00881

Gnomad4 AMR exome AF: 0.0212

Gnomad4 ASJ exome AF: 0.0566

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0331

Gnomad4 FIN exome AF: 0.0602

Gnomad4 NFE exome AF: 0.0643

Gnomad4 OTH exome AF: 0.0518

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

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.0287

Gnomad4 ASJ AF: 0.0547

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0277

Gnomad4 FIN AF: 0.0602

Gnomad4 NFE AF: 0.0663

Gnomad4 OTH AF: 0.0336

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2016	- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.3
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs45442394; hg19: chr20-61980994;