rs146751925

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000742.4(CHRNA2):c.731A>G(p.Lys244Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,604,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

CHRNA2
NM_000742.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 8.02

Publications

1 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
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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15419382).

BP6

Variant 8-27463712-T-C is Benign according to our data. Variant chr8-27463712-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 204965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 72 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNA2	NM_000742.4	MANE Select	c.731A>G	p.Lys244Arg	missense	Exon 6 of 7	NP_000733.2	Q15822-1
CHRNA2	NM_001282455.2		c.686A>G	p.Lys229Arg	missense	Exon 6 of 7	NP_001269384.1	Q15822-2
CHRNA2	NM_001347705.2		c.254A>G	p.Lys85Arg	missense	Exon 6 of 7	NP_001334634.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.731A>G	p.Lys244Arg	missense	Exon 6 of 7	ENSP00000385026.1	Q15822-1
CHRNA2	ENST00000523695.5	TSL:1	n.*133A>G		non_coding_transcript_exon	Exon 6 of 7	ENSP00000430612.1	E5RJ54
CHRNA2	ENST00000523695.5	TSL:1	n.*133A>G		3_prime_UTR	Exon 6 of 7	ENSP00000430612.1	E5RJ54

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

145934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00152

GnomAD2 exomes

AF:

0.000119

AC:

AN:

251464

AF XY:

0.0000883

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000569

AC:

AN:

1458470

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

725506

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

33464

American (AMR)

AF:

0.000135

AC:

AN:

44528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

37674

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111098

Other (OTH)

AF:

0.0000829

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000493

AC:

AN:

146056

Hom.:

Cov.:

AF XY:

0.000392

AC XY:

AN XY:

71368

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

39198

American (AMR)

AF:

0.000135

AC:

AN:

14778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3338

East Asian (EAS)

AF:

0.00

AC:

AN:

4818

South Asian (SAS)

AF:

0.00

AC:

AN:

4596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65712

Other (OTH)

AF:

0.00151

AC:

AN:

1988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000129

Hom.:

Bravo

AF:

0.000514

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autosomal dominant nocturnal frontal lobe epilepsy (1)

CHRNA2-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.035

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.9

PhyloP100

8.0

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.49

Sift

Benign

0.23

Sift4G

Benign

0.37

Polyphen

0.33

Vest4

0.77

MVP

0.83

MPC

0.66

ClinPred

0.12

GERP RS

5.0

Varity_R

0.37

gMVP

0.68

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: 0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over