chr8-27467305-T-C

Position:

chr8-27467305-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000742.4(CHRNA2):c.373A>G(p.Thr125Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,609,834 control chromosomes in the GnomAD database, including 212,156 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26939 hom., cov: 33)

Exomes 𝑓: 0.50 ( 185217 hom. )

Consequence

CHRNA2
NM_000742.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.868

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.8624587E-6).

BP6

Variant 8-27467305-T-C is Benign according to our data. Variant chr8-27467305-T-C is described in ClinVar as [Benign]. Clinvar id is 128739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA2	NM_000742.4 linkuse as main transcript	c.373A>G	p.Thr125Ala	missense_variant	5/7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3 linkuse as main transcript	c.373A>G	p.Thr125Ala	missense_variant	5/7	5	NM_000742.4	ENSP00000385026	P2	Q15822-1

Frequencies

GnomAD3 genomes

AF:

0.581

AC:

88351

AN:

152006

Hom.:

26890

Cov.:

show subpopulations

Gnomad AFR

AF:

0.765

Gnomad AMI

AF:

0.361

Gnomad AMR

AF:

0.582

Gnomad ASJ

AF:

0.526

Gnomad EAS

AF:

0.646

Gnomad SAS

AF:

0.418

Gnomad FIN

AF:

0.523

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.491

Gnomad OTH

AF:

0.559

GnomAD3 exomes

AF:

0.529

AC:

133044

AN:

251418

Hom.:

36419

AF XY:

0.516

AC XY:

70064

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.775

Gnomad AMR exome

AF:

0.591

Gnomad ASJ exome

AF:

0.515

Gnomad EAS exome

AF:

0.644

Gnomad SAS exome

AF:

0.398

Gnomad FIN exome

AF:

0.525

Gnomad NFE exome

AF:

0.495

Gnomad OTH exome

AF:

0.514

GnomAD4 exome

AF:

0.498

AC:

726432

AN:

1457710

Hom.:

185217

Cov.:

AF XY:

0.495

AC XY:

359210

AN XY:

725488

show subpopulations

Gnomad4 AFR exome

AF:

0.779

Gnomad4 AMR exome

AF:

0.585

Gnomad4 ASJ exome

AF:

0.519

Gnomad4 EAS exome

AF:

0.687

Gnomad4 SAS exome

AF:

0.396

Gnomad4 FIN exome

AF:

0.524

Gnomad4 NFE exome

AF:

0.486

Gnomad4 OTH exome

AF:

0.507

GnomAD4 genome

AF:

0.581

AC:

88454

AN:

152124

Hom.:

26939

Cov.:

AF XY:

0.582

AC XY:

43260

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.766

Gnomad4 AMR

AF:

0.582

Gnomad4 ASJ

AF:

0.526

Gnomad4 EAS

AF:

0.646

Gnomad4 SAS

AF:

0.419

Gnomad4 FIN

AF:

0.523

Gnomad4 NFE

AF:

0.491

Gnomad4 OTH

AF:

0.553

Alfa

AF:

0.512

Hom.:

52722

Bravo

AF:

0.593

TwinsUK

AF:

0.486

AC:

1802

ALSPAC

AF:

0.468

AC:

1805

ESP6500AA

AF:

0.762

AC:

3356

ESP6500EA

AF:

0.487

AC:

4189

ExAC

AF:

0.531

AC:

64459

Asia WGS

AF:

0.518

AC:

1802

AN:

3478

EpiCase

AF:

0.487

EpiControl

AF:

0.490

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	Eurofins Ntd Llc (ga)	Jan 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2013	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. -
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 80% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 74. Only high quality variants are reported. -

Autosomal dominant nocturnal frontal lobe epilepsy 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.27

DEOGEN2

Benign

0.15

T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.40

T;T;T

MetaRNN

Benign

0.0000019

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.1

N;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.44

PROVEAN

Benign

0.47

N;.;N

REVEL

Benign

0.13

Sift

Benign

0.81

T;.;T

Sift4G

Benign

0.82

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.036

MPC

0.18

ClinPred

0.0034

GERP RS

3.5

Varity_R

0.072

gMVP

0.19

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