rs735421

Variant names:

• chr8-27461775-A-G
• rs735421
• NM_000742.4:c.1465-21T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-27461775-A-G
• chr8-27461775-A-T

Variant summary

Our verdict is Benign. The variant received -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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.1465-21T>C		intron_variant	Intron 6 of 6	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.1465-21T>C		intron_variant	Intron 6 of 6	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

GnomAD2 exomes AF: 0.310 AC: 77683 AN: 250436 AF XY: 0.310

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 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 AC: 4150 AN: 33472

Gnomad4 AMR exome AF: 0.351 AC: 15709 AN: 44714

Gnomad4 ASJ exome AF: 0.367 AC: 9602 AN: 26132

Gnomad4 EAS exome AF: 0.293 AC: 11614 AN: 39688

Gnomad4 SAS exome AF: 0.247 AC: 21286 AN: 86246

Gnomad4 FIN exome AF: 0.372 AC: 19874 AN: 53360

Gnomad4 NFE exome AF: 0.321 AC: 357073 AN: 1111624

Gnomad4 Remaining exome AF: 0.304 AC: 18363 AN: 60354

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 AC: 0.127738 AN: 0.127738

Gnomad4 AMR AF: 0.329 AC: 0.329042 AN: 0.329042

Gnomad4 ASJ AF: 0.382 AC: 0.382421 AN: 0.382421

Gnomad4 EAS AF: 0.241 AC: 0.240641 AN: 0.240641

Gnomad4 SAS AF: 0.256 AC: 0.256432 AN: 0.256432

Gnomad4 FIN AF: 0.376 AC: 0.375566 AN: 0.375566

Gnomad4 NFE AF: 0.328 AC: 0.328223 AN: 0.328223

Gnomad4 OTH AF: 0.290 AC: 0.290323 AN: 0.290323

Alfa AF: 0.318 Hom.: 10613

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

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. -

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 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
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

Publications

LitVar

Other links and lift over

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