chr8-27469889-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000742.4(CHRNA2):c.166A>T(p.Thr56Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T56T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CHRNA2
NM_000742.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.636

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011084735).

BP6

Variant 8-27469889-T-A is Benign according to our data. Variant chr8-27469889-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289277.

BS2

High AC in GnomAd4 at 51 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
CHRNA2	NM_000742.4	MANE Select	c.166A>T	p.Thr56Ser	missense	Exon 3 of 7	NP_000733.2
CHRNA2	NM_001282455.2		c.166A>T	p.Thr56Ser	missense	Exon 3 of 7	NP_001269384.1
CHRNA2	NM_001347705.2		c.-262A>T		5_prime_UTR	Exon 3 of 7	NP_001334634.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.166A>T	p.Thr56Ser	missense	Exon 3 of 7	ENSP00000385026.1
CHRNA2	ENST00000523695.5	TSL:1	n.166A>T		non_coding_transcript_exon	Exon 3 of 7	ENSP00000430612.1
CHRNA2	ENST00000240132.7	TSL:2	c.166A>T	p.Thr56Ser	missense	Exon 3 of 7	ENSP00000240132.2

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

GnomAD2 exomes

AF:

0.0000716

AC:

AN:

251368

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00

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:

0.0000233

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000335

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41442

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

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:

0.0000868

Hom.:

Bravo

AF:

0.000412

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autosomal dominant nocturnal frontal lobe epilepsy (1)

Autosomal dominant nocturnal frontal lobe epilepsy 4 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.11

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.072

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.039

M_CAP

Benign

0.0054

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.64

PrimateAI

Benign

0.37

PROVEAN

Benign

0.67

REVEL

Benign

0.048

Sift

Benign

0.84

Sift4G

Benign

0.84

Polyphen

0.0

Vest4

0.13

MutPred

0.21

Gain of phosphorylation at T56 (P = 0.0851)

MVP

0.28

MPC

0.16

ClinPred

0.010

GERP RS

0.29

Varity_R

0.026

gMVP

0.20

Mutation Taster

=98/2

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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