20-63346437-G-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000744.7(CHRNA4):​c.*301C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000869 in 575,692 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 Benign (★).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00092 ( 0 hom. )

Consequence

CHRNA4
NM_000744.7 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.638

Publications

0 publications found
Variant links:
Genes affected
CHRNA4 (HGNC:1958): (cholinergic receptor nicotinic alpha 4 subunit) This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]
CHRNA4 Gene-Disease associations (from GenCC):
  • autosomal dominant nocturnal frontal lobe epilepsy 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • familial sleep-related hypermotor epilepsy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • autosomal dominant nocturnal frontal lobe epilepsy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
Variant 20-63346437-G-A is Benign according to our data. Variant chr20-63346437-G-A is described in ClinVar as [Benign]. Clinvar id is 1233246.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 109 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRNA4NM_000744.7 linkc.*301C>T 3_prime_UTR_variant Exon 6 of 6 ENST00000370263.9 NP_000735.1 P43681-1B4DK78Q59FV0
CHRNA4NR_046317.2 linkn.2394C>T non_coding_transcript_exon_variant Exon 6 of 6
CHRNA4NM_001256573.2 linkc.*301C>T 3_prime_UTR_variant Exon 6 of 6 NP_001243502.1 P43681Q4VAQ3B4DK78Q59FV0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRNA4ENST00000370263.9 linkc.*301C>T 3_prime_UTR_variant Exon 6 of 6 1 NM_000744.7 ENSP00000359285.4 P43681-1

Frequencies

GnomAD3 genomes
AF:
0.000723
AC:
110
AN:
152156
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.000565
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00128
Gnomad OTH
AF:
0.000479
GnomAD2 exomes
AF:
0.000705
AC:
92
AN:
130494
AF XY:
0.000632
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000246
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00130
Gnomad NFE exome
AF:
0.00127
Gnomad OTH exome
AF:
0.000999
GnomAD4 exome
AF:
0.000923
AC:
391
AN:
423416
Hom.:
0
Cov.:
0
AF XY:
0.000906
AC XY:
211
AN XY:
232860
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
12770
American (AMR)
AF:
0.000293
AC:
9
AN:
30688
Ashkenazi Jewish (ASJ)
AF:
0.0000626
AC:
1
AN:
15974
East Asian (EAS)
AF:
0.00
AC:
0
AN:
20872
South Asian (SAS)
AF:
0.000675
AC:
41
AN:
60770
European-Finnish (FIN)
AF:
0.00125
AC:
26
AN:
20744
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1824
European-Non Finnish (NFE)
AF:
0.00126
AC:
298
AN:
237144
Other (OTH)
AF:
0.000707
AC:
16
AN:
22630
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
31
61
92
122
153
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
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:
0.000716
AC:
109
AN:
152276
Hom.:
0
Cov.:
33
AF XY:
0.000564
AC XY:
42
AN XY:
74434
show subpopulations
African (AFR)
AF:
0.000265
AC:
11
AN:
41560
American (AMR)
AF:
0.000131
AC:
2
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5162
South Asian (SAS)
AF:
0.000622
AC:
3
AN:
4826
European-Finnish (FIN)
AF:
0.000565
AC:
6
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00128
AC:
87
AN:
68010
Other (OTH)
AF:
0.00
AC:
0
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
6
12
17
23
29
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<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:
0.000897
Hom.:
0
Bravo
AF:
0.000661
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Feb 14, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.91
CADD
Benign
0.88
DANN
Benign
0.47
PhyloP100
-0.64
Mutation Taster
=100/0
polymorphism

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: rs201041492; hg19: chr20-61977789; API