chr8-27464080-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000742.4(CHRNA2):c.450-87C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,517,462 control chromosomes in the GnomAD database, including 543,356 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.82 ( 51568 hom., cov: 31)

Exomes 𝑓: 0.85 ( 491788 hom. )

Consequence

CHRNA2
NM_000742.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.02

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant nocturnal frontal lobe epilepsy 4
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial sleep-related hypermotor epilepsy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
benign familial infantile epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CHRNA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 8-27464080-G-C is Benign according to our data. Variant chr8-27464080-G-C is described in ClinVar as [Benign]. Clinvar id is 670757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4 link	c.450-87C>G		intron_variant	Intron 5 of 6	ENST00000407991.3	NP_000733.2	Q15822-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3 link	c.450-87C>G		intron_variant	Intron 5 of 6	5	NM_000742.4	ENSP00000385026.1		Q15822-1

Frequencies

GnomAD3 genomes

AF:

0.821

AC:

124736

AN:

151988

Hom.:

51536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.776

Gnomad AMI

AF:

0.877

Gnomad AMR

AF:

0.808

Gnomad ASJ

AF:

0.935

Gnomad EAS

AF:

0.555

Gnomad SAS

AF:

0.850

Gnomad FIN

AF:

0.836

Gnomad MID

AF:

0.937

Gnomad NFE

AF:

0.859

Gnomad OTH

AF:

0.846

GnomAD4 exome

AF:

0.847

AC:

1156463

AN:

1365356

Hom.:

491788

AF XY:

0.848

AC XY:

576511

AN XY:

679882

show subpopulations

African (AFR)

AF:

0.776

AC:

24173

AN:

31156

American (AMR)

AF:

0.809

AC:

31342

AN:

38762

Ashkenazi Jewish (ASJ)

AF:

0.925

AC:

23266

AN:

25158

East Asian (EAS)

AF:

0.573

AC:

21269

AN:

37118

South Asian (SAS)

AF:

0.868

AC:

70581

AN:

81322

European-Finnish (FIN)

AF:

0.836

AC:

42183

AN:

50462

Middle Eastern (MID)

AF:

0.924

AC:

3788

AN:

4098

European-Non Finnish (NFE)

AF:

0.857

AC:

891742

AN:

1040376

Other (OTH)

AF:

0.846

AC:

48119

AN:

56904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

9298

18595

27893

37190

46488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19522

39044

58566

78088

97610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.821

AC:

124820

AN:

152106

Hom.:

51568

Cov.:

AF XY:

0.818

AC XY:

60823

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.775

AC:

32157

AN:

41470

American (AMR)

AF:

0.808

AC:

12345

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.935

AC:

3248

AN:

3472

East Asian (EAS)

AF:

0.554

AC:

2857

AN:

5154

South Asian (SAS)

AF:

0.849

AC:

4096

AN:

4826

European-Finnish (FIN)

AF:

0.836

AC:

8858

AN:

10602

Middle Eastern (MID)

AF:

0.932

AC:

274

AN:

294

European-Non Finnish (NFE)

AF:

0.859

AC:

58401

AN:

67990

Other (OTH)

AF:

0.847

AC:

1784

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1099

2198

3297

4396

5495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.811

Hom.:

2556

Bravo

AF:

0.817

Asia WGS

AF:

0.716

AC:

2490

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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 54% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 50. Only high quality variants are reported. -

Autosomal dominant nocturnal frontal lobe epilepsy 4

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.81

(source)

DANN

Benign

0.56

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over