rs2273505

Variant names:

• chr20-63359526-C-T
• rs2273505
• NM_000744.7:c.228+22G>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.228+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0791 in 1,612,242 control chromosomes in the GnomAD database, including 5,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (744 hom., cov: 34)
  • Exomes 𝑓: 0.077 (5140 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.30

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=-1.0).
• BP6: Variant 20-63359526-C-T is Benign according to our data. Variant chr20-63359526-C-T is described in ClinVar as [Benign]. Clinvar id is 1251570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63359526-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.228+22G>A		intron_variant	Intron 2 of 5	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-319+22G>A		intron_variant	Intron 2 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.412+22G>A		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.228+22G>A		intron_variant	Intron 2 of 5	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.0955 AC: 14534 AN: 152138 Hom.: 743 Cov.: 34

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0765

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0870

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.0918 AC: 22896 AN: 249412 Hom.: 1233 AF XY: 0.0948 AC XY: 12841 AN XY: 135462

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0479

Gnomad ASJ exome AF: 0.0964

Gnomad EAS exome AF: 0.124

Gnomad SAS exome AF: 0.164

Gnomad FIN exome AF: 0.0886

Gnomad NFE exome AF: 0.0746

Gnomad OTH exome AF: 0.0909

GnomAD4 exome AF: 0.0774 AC: 112965 AN: 1459986 Hom.: 5140 Cov.: 38 AF XY: 0.0797 AC XY: 57902 AN XY: 726300

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.0512

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.0869

Gnomad4 NFE exome AF: 0.0668

Gnomad4 OTH exome AF: 0.0845

GnomAD4 genome AF: 0.0956 AC: 14556 AN: 152256 Hom.: 744 Cov.: 34 AF XY: 0.0965 AC XY: 7183 AN XY: 74442

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0765

Gnomad4 ASJ AF: 0.0888

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.0870

Gnomad4 NFE AF: 0.0713

Gnomad4 OTH AF: 0.103

Alfa AF: 0.0836 Hom.: 121

Bravo AF: 0.0941

Asia WGS AF: 0.143 AC: 496 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.18
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2273505; hg19: chr20-61990878;