rs735421

Positions:

• chr8-27461775-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000742.4(CHRNA2):​c.1465-21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,613,550 control chromosomes in the GnomAD database, including 80,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6435 hom., cov: 33)
  • Exomes 𝑓: 0.31 (73884 hom.)
• Consequence: CHRNA2 NM_000742.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.240

Genes affected

CHRNA2 (HGNC:1956): (cholinergic receptor nicotinic alpha 2 subunit) Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels formed by a pentameric arrangement of alpha and beta subunits to create distinct muscle and neuronal receptors. Neuronal receptors are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. This gene encodes an alpha subunit that is widely expressed in the brain. The proposed structure for nAChR subunits is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. Mutations in this gene cause autosomal dominant nocturnal frontal lobe epilepsy type 4. Single nucleotide polymorphisms (SNPs) in this gene have been associated with nicotine dependence. [provided by RefSeq, Nov 2009]

CHRNA2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-27461775-A-G is Benign according to our data. Variant chr8-27461775-A-G is described in ClinVar as [Benign]. Clinvar id is 670848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.1465-21T>C		intron_variant		ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.1465-21T>C		intron_variant		5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41334 AN: 152086 Hom.: 6429 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.294

GnomAD3 exomes AF: 0.310 AC: 77683 AN: 250436 Hom.: 12662 AF XY: 0.310 AC XY: 41992 AN XY: 135454

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.230

Gnomad SAS exome AF: 0.248

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.315 AC: 459696 AN: 1461346 Hom.: 73884 Cov.: 35 AF XY: 0.314 AC XY: 228139 AN XY: 726984

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.351

Gnomad4 ASJ exome AF: 0.367

Gnomad4 EAS exome AF: 0.293

Gnomad4 SAS exome AF: 0.247

Gnomad4 FIN exome AF: 0.372

Gnomad4 NFE exome AF: 0.321

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.272 AC: 41357 AN: 152204 Hom.: 6435 Cov.: 33 AF XY: 0.274 AC XY: 20412 AN XY: 74412

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.241

Gnomad4 SAS AF: 0.256

Gnomad4 FIN AF: 0.376

Gnomad4 NFE AF: 0.328

Gnomad4 OTH AF: 0.290

Alfa AF: 0.325 Hom.: 8487

Bravo AF: 0.262

Asia WGS AF: 0.224 AC: 779 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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. -

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 62% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 58. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.71

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: rs735421; hg19: chr8-27319292; COSMIC: COSV53558381; COSMIC: COSV53558381;