chr20-63359522-T-C

Position:

• chr20-63359522-T-C

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.228+26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.942 in 1,612,210 control chromosomes in the GnomAD database, including 718,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59636 hom., cov: 33)
  • Exomes 𝑓: 0.95 (658406 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.435

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 20-63359522-T-C is Benign according to our data. Variant chr20-63359522-T-C is described in ClinVar as [Benign]. Clinvar id is 670759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63359522-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.228+26A>G		intron_variant		ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-319+26A>G		intron_variant			NP_001243502.1
CHRNA4	NR_046317.2	n.412+26A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.228+26A>G		intron_variant		1	NM_000744.7	ENSP00000359285	P1

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133184 AN: 152098 Hom.: 59606 Cov.: 33

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.925

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.980

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.953

Gnomad OTH AF: 0.891

GnomAD3 exomes AF: 0.939 AC: 234117 AN: 249274 Hom.: 110718 AF XY: 0.943 AC XY: 127717 AN XY: 135390

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.965

Gnomad ASJ exome AF: 0.923

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.952

Gnomad FIN exome AF: 0.977

Gnomad NFE exome AF: 0.953

Gnomad OTH exome AF: 0.943

GnomAD4 exome AF: 0.948 AC: 1384755 AN: 1459994 Hom.: 658406 Cov.: 49 AF XY: 0.949 AC XY: 689538 AN XY: 726300

Gnomad4 AFR exome AF: 0.655

Gnomad4 AMR exome AF: 0.962

Gnomad4 ASJ exome AF: 0.925

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.951

Gnomad4 FIN exome AF: 0.975

Gnomad4 NFE exome AF: 0.955

Gnomad4 OTH exome AF: 0.938

GnomAD4 genome AF: 0.876 AC: 133268 AN: 152216 Hom.: 59636 Cov.: 33 AF XY: 0.882 AC XY: 65593 AN XY: 74410

Gnomad4 AFR AF: 0.666

Gnomad4 AMR AF: 0.939

Gnomad4 ASJ AF: 0.925

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.956

Gnomad4 FIN AF: 0.980

Gnomad4 NFE AF: 0.953

Gnomad4 OTH AF: 0.892

Alfa AF: 0.891 Hom.: 12399

Bravo AF: 0.862

Asia WGS AF: 0.964 AC: 3351 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 93. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.30
DANN	Benign	0.36

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: rs6090384; hg19: chr20-61990874;