8-27461027-A-G

Variant names:

Variant summary

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

The ENST00000520600.1(CHRNA2):n.1017T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 154,438 control chromosomes in the GnomAD database, including 55,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.85 ( 55121 hom., cov: 30)

Exomes 𝑓: 0.84 ( 860 hom. )

Consequence

CHRNA2
ENST00000520600.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.68

Publications

8 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=-0.97).

BP6

Variant 8-27461027-A-G is Benign according to our data. Variant chr8-27461027-A-G is described in CliVar as Benign. Clinvar id is 362685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4 link	c.*602T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000407991.3	NP_000733.2	Q15822-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHRNA2	ENST00000520600.1 link	n.1017T>C	non_coding_transcript_exon_variant	Exon 2 of 2	1
CHRNA2	ENST00000407991.3 link	c.*602T>C	3_prime_UTR_variant	Exon 7 of 7	5	NM_000742.4	ENSP00000385026.1	Q15822-1
CHRNA2	ENST00000523695.5 link	n.*1594T>C	downstream_gene_variant		1		ENSP00000430612.1	E5RJ54
CHRNA2	ENST00000520933.7 link	c.*602T>C	downstream_gene_variant		5		ENSP00000429616.2	A0A0X1KG79

Frequencies

GnomAD3 genomes

AF:

0.849

AC:

128951

AN:

151930

Hom.:

55092

Cov.:

show subpopulations

Gnomad AFR

AF:

0.870

Gnomad AMI

AF:

0.911

Gnomad AMR

AF:

0.818

Gnomad ASJ

AF:

0.936

Gnomad EAS

AF:

0.532

Gnomad SAS

AF:

0.847

Gnomad FIN

AF:

0.837

Gnomad MID

AF:

0.946

Gnomad NFE

AF:

0.862

Gnomad OTH

AF:

0.871

GnomAD4 exome

AF:

0.835

AC:

1994

AN:

2388

Hom.:

860

Cov.:

AF XY:

0.834

AC XY:

1207

AN XY:

1448

show subpopulations

African (AFR)

AF:

0.909

AC:

AN:

American (AMR)

AF:

0.786

AC:

272

AN:

346

Ashkenazi Jewish (ASJ)

AF:

0.889

AC:

AN:

East Asian (EAS)

AF:

0.485

AC:

AN:

South Asian (SAS)

AF:

0.860

AC:

117

AN:

136

European-Finnish (FIN)

AF:

0.848

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.857

AC:

1411

AN:

1646

Other (OTH)

AF:

0.794

AC:

AN:

102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.849

AC:

129031

AN:

152050

Hom.:

55121

Cov.:

AF XY:

0.844

AC XY:

62743

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.870

AC:

36084

AN:

41476

American (AMR)

AF:

0.818

AC:

12514

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.936

AC:

3247

AN:

3470

East Asian (EAS)

AF:

0.531

AC:

2734

AN:

5144

South Asian (SAS)

AF:

0.846

AC:

4064

AN:

4804

European-Finnish (FIN)

AF:

0.837

AC:

8855

AN:

10584

Middle Eastern (MID)

AF:

0.942

AC:

277

AN:

294

European-Non Finnish (NFE)

AF:

0.862

AC:

58589

AN:

67964

Other (OTH)

AF:

0.873

AC:

1836

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

974

1947

2921

3894

4868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

888

1776

2664

3552

4440

<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:

0.845

Hom.:

4340

Bravo

AF:

0.850

Asia WGS

AF:

0.725

AC:

2524

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal dominant nocturnal frontal lobe epilepsy 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

-0.97

CADD

Benign

0.11

(source)

DANN

Benign

0.77

PhyloP100

-3.7

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