NM_000742.4:c.1465-21T>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.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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.240

Publications

11 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=-0.84).

BP6

Variant 8-27461775-A-G is Benign according to our data. Variant chr8-27461775-A-G is described in ClinVar as Benign. ClinVar VariationId 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 link	c.1465-21T>C		intron_variant	Intron 6 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.1465-21T>C		intron_variant	Intron 6 of 6	5	NM_000742.4	ENSP00000385026.1		Q15822-1

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

41334

AN:

152086

Hom.:

6429

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.314

AC XY:

228139

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.124

AC:

4150

AN:

33472

American (AMR)

AF:

0.351

AC:

15709

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

9602

AN:

26132

East Asian (EAS)

AF:

0.293

AC:

11614

AN:

39688

South Asian (SAS)

AF:

0.247

AC:

21286

AN:

86246

European-Finnish (FIN)

AF:

0.372

AC:

19874

AN:

53360

Middle Eastern (MID)

AF:

0.352

AC:

2025

AN:

5756

European-Non Finnish (NFE)

AF:

0.321

AC:

357073

AN:

1111624

Other (OTH)

AF:

0.304

AC:

18363

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

16997

33994

50992

67989

84986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11412

22824

34236

45648

57060

<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:

0.272

AC:

41357

AN:

152204

Hom.:

6435

Cov.:

AF XY:

0.274

AC XY:

20412

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.128

AC:

5307

AN:

41546

American (AMR)

AF:

0.329

AC:

5035

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.382

AC:

1327

AN:

3470

East Asian (EAS)

AF:

0.241

AC:

1247

AN:

5182

South Asian (SAS)

AF:

0.256

AC:

1236

AN:

4820

European-Finnish (FIN)

AF:

0.376

AC:

3981

AN:

10600

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.328

AC:

22310

AN:

67972

Other (OTH)

AF:

0.290

AC:

612

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1533

3066

4598

6131

7664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

426

852

1278

1704

2130

<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:

0.318

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

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 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

(source)

DANN

Benign

0.71

PhyloP100

-0.24

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