8-27459820-A-G

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.*1809T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 152,306 control chromosomes in the GnomAD database, including 56,264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 56236 hom., cov: 32)
Exomes 𝑓: 0.83 ( 28 hom. )

Consequence

CHRNA2
NM_000742.4 3_prime_UTR

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -3.83

Publications

17 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

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=-0.99).
BP6
Variant 8-27459820-A-G is Benign according to our data. Variant chr8-27459820-A-G is described in ClinVar as [Benign]. Clinvar id is 362664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRNA2NM_000742.4 linkc.*1809T>C 3_prime_UTR_variant Exon 7 of 7 ENST00000407991.3 NP_000733.2 Q15822-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRNA2ENST00000407991.3 linkc.*1809T>C 3_prime_UTR_variant Exon 7 of 7 5 NM_000742.4 ENSP00000385026.1 Q15822-1

Frequencies

GnomAD3 genomes
AF:
0.857
AC:
130373
AN:
152100
Hom.:
56189
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.896
Gnomad AMI
AF:
0.911
Gnomad AMR
AF:
0.821
Gnomad ASJ
AF:
0.934
Gnomad EAS
AF:
0.580
Gnomad SAS
AF:
0.850
Gnomad FIN
AF:
0.836
Gnomad MID
AF:
0.946
Gnomad NFE
AF:
0.861
Gnomad OTH
AF:
0.875
GnomAD4 exome
AF:
0.826
AC:
71
AN:
86
Hom.:
28
Cov.:
0
AF XY:
0.875
AC XY:
42
AN XY:
48
show subpopulations
African (AFR)
AC:
0
AN:
0
American (AMR)
AF:
0.750
AC:
3
AN:
4
Ashkenazi Jewish (ASJ)
AF:
0.500
AC:
2
AN:
4
East Asian (EAS)
AF:
0.750
AC:
3
AN:
4
South Asian (SAS)
AC:
0
AN:
0
European-Finnish (FIN)
AF:
0.800
AC:
16
AN:
20
Middle Eastern (MID)
AC:
0
AN:
0
European-Non Finnish (NFE)
AF:
0.833
AC:
35
AN:
42
Other (OTH)
AF:
1.00
AC:
12
AN:
12
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<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:
0.857
AC:
130474
AN:
152220
Hom.:
56236
Cov.:
32
AF XY:
0.853
AC XY:
63453
AN XY:
74412
show subpopulations
African (AFR)
AF:
0.896
AC:
37200
AN:
41538
American (AMR)
AF:
0.821
AC:
12552
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.934
AC:
3242
AN:
3472
East Asian (EAS)
AF:
0.580
AC:
2992
AN:
5160
South Asian (SAS)
AF:
0.848
AC:
4097
AN:
4830
European-Finnish (FIN)
AF:
0.836
AC:
8855
AN:
10594
Middle Eastern (MID)
AF:
0.942
AC:
277
AN:
294
European-Non Finnish (NFE)
AF:
0.861
AC:
58575
AN:
68012
Other (OTH)
AF:
0.877
AC:
1853
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
939
1878
2818
3757
4696
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
892
1784
2676
3568
4460
<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:
0.860
Hom.:
241948
Bravo
AF:
0.859
Asia WGS
AF:
0.743
AC:
2586
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 12, 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
-0.99
CADD
Benign
0.032
DANN
Benign
0.34
PhyloP100
-3.8
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs2280375; hg19: chr8-27317337; API