8-27460470-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.*1159T>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 0.412 in 152,172 control chromosomes in the GnomAD database, including 13,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13770 hom., cov: 31)
Exomes 𝑓: 0.44 ( 14 hom. )

Consequence

CHRNA2
NM_000742.4 3_prime_UTR

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 0.183

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

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=-0.91).
BP6
Variant 8-27460470-A-G is Benign according to our data. Variant chr8-27460470-A-G is described in ClinVar as [Benign]. Clinvar id is 362673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRNA2NM_000742.4 linkc.*1159T>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.*1159T>C 3_prime_UTR_variant Exon 7 of 7 5 NM_000742.4 ENSP00000385026.1 Q15822-1
CHRNA2ENST00000520600.1 linkn.*106T>C downstream_gene_variant 1

Frequencies

GnomAD3 genomes
AF:
0.412
AC:
62535
AN:
151896
Hom.:
13762
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.253
Gnomad AMI
AF:
0.353
Gnomad AMR
AF:
0.433
Gnomad ASJ
AF:
0.645
Gnomad EAS
AF:
0.352
Gnomad SAS
AF:
0.412
Gnomad FIN
AF:
0.530
Gnomad MID
AF:
0.585
Gnomad NFE
AF:
0.476
Gnomad OTH
AF:
0.464
GnomAD4 exome
AF:
0.436
AC:
68
AN:
156
Hom.:
14
Cov.:
0
AF XY:
0.434
AC XY:
53
AN XY:
122
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
2
American (AMR)
AC:
0
AN:
0
Ashkenazi Jewish (ASJ)
AF:
0.750
AC:
3
AN:
4
East Asian (EAS)
AF:
0.500
AC:
2
AN:
4
South Asian (SAS)
AC:
0
AN:
0
European-Finnish (FIN)
AF:
0.300
AC:
3
AN:
10
Middle Eastern (MID)
AF:
0.250
AC:
1
AN:
4
European-Non Finnish (NFE)
AF:
0.426
AC:
52
AN:
122
Other (OTH)
AF:
0.700
AC:
7
AN:
10
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.510
Heterozygous variant carriers
0
4
7
11
14
18
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:
0.412
AC:
62571
AN:
152016
Hom.:
13770
Cov.:
31
AF XY:
0.413
AC XY:
30708
AN XY:
74308
show subpopulations
African (AFR)
AF:
0.253
AC:
10496
AN:
41456
American (AMR)
AF:
0.433
AC:
6626
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.645
AC:
2241
AN:
3472
East Asian (EAS)
AF:
0.352
AC:
1813
AN:
5144
South Asian (SAS)
AF:
0.410
AC:
1975
AN:
4816
European-Finnish (FIN)
AF:
0.530
AC:
5607
AN:
10586
Middle Eastern (MID)
AF:
0.582
AC:
171
AN:
294
European-Non Finnish (NFE)
AF:
0.476
AC:
32335
AN:
67936
Other (OTH)
AF:
0.469
AC:
987
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1792
3583
5375
7166
8958
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
594
1188
1782
2376
2970
<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:
0.451
Hom.:
25419
Bravo
AF:
0.400
Asia WGS
AF:
0.382
AC:
1326
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
-0.91
CADD
Benign
1.7
DANN
Benign
0.63
PhyloP100
0.18
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: rs1560344; hg19: chr8-27317987; API