rs56298562

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000742.4(CHRNA2):c.1324C>T(p.Leu442=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,608,776 control chromosomes in the GnomAD database, including 678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 46 hom., cov: 33)

Exomes 𝑓: 0.026 ( 632 hom. )

Consequence

CHRNA2
NM_000742.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.05

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 8-27463119-G-A is Benign according to our data. Variant chr8-27463119-G-A is described in ClinVar as [Benign]. Clinvar id is 128737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-27463119-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=3.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0178 (2710/152350) while in subpopulation SAS AF= 0.03 (145/4830). AF 95% confidence interval is 0.026. There are 46 homozygotes in gnomad4. There are 1377 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd at 2713 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA2	NM_000742.4 linkuse as main transcript	c.1324C>T	p.Leu442=	synonymous_variant	6/7	ENST00000407991.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA2	ENST00000407991.3 linkuse as main transcript	c.1324C>T	p.Leu442=	synonymous_variant	6/7	5	NM_000742.4	P2	Q15822-1

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2713

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00374

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0302

Gnomad FIN

AF:

0.0370

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0224

AC:

5608

AN:

250796

Hom.:

100

AF XY:

0.0245

AC XY:

3321

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00894

Gnomad ASJ exome

AF:

0.0228

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0396

Gnomad FIN exome

AF:

0.0352

Gnomad NFE exome

AF:

0.0257

Gnomad OTH exome

AF:

0.0203

GnomAD4 exome

AF:

0.0261

AC:

37969

AN:

1456426

Hom.:

632

Cov.:

AF XY:

0.0265

AC XY:

19152

AN XY:

723252

show subpopulations

Gnomad4 AFR exome

AF:

0.00404

Gnomad4 AMR exome

AF:

0.00903

Gnomad4 ASJ exome

AF:

0.0222

Gnomad4 EAS exome

AF:

0.000911

Gnomad4 SAS exome

AF:

0.0398

Gnomad4 FIN exome

AF:

0.0354

Gnomad4 NFE exome

AF:

0.0271

Gnomad4 OTH exome

AF:

0.0226

GnomAD4 genome

AF:

0.0178

AC:

2710

AN:

152350

Hom.:

Cov.:

AF XY:

0.0185

AC XY:

1377

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00373

Gnomad4 AMR

AF:

0.0144

Gnomad4 ASJ

AF:

0.0268

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0300

Gnomad4 FIN

AF:

0.0370

Gnomad4 NFE

AF:

0.0244

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0220

Hom.:

Bravo

AF:

0.0152

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0238

EpiControl

AF:

0.0249

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 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. -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal dominant nocturnal frontal lobe epilepsy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

Cadd

Benign

0.76

Dann

Benign

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over