20-63359551-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001256573.2(CHRNA4):​c.-322C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,612,656 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 0.00048 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CHRNA4
NM_001256573.2 5_prime_UTR_premature_start_codon_gain

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -1.15
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
Variant 20-63359551-G-A is Benign according to our data. Variant chr20-63359551-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63359551-G-A is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 73 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CHRNA4NM_000744.7 linkc.225C>T p.Asp75Asp synonymous_variant 2/6 ENST00000370263.9 NP_000735.1 P43681-1B4DK78Q59FV0
CHRNA4NM_001256573.2 linkc.-322C>T 5_prime_UTR_premature_start_codon_gain_variant 2/6 NP_001243502.1 P43681Q4VAQ3B4DK78Q59FV0
CHRNA4NM_001256573.2 linkc.-322C>T 5_prime_UTR_variant 2/6 NP_001243502.1 P43681Q4VAQ3B4DK78Q59FV0
CHRNA4NR_046317.2 linkn.409C>T non_coding_transcript_exon_variant 2/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CHRNA4ENST00000370263.9 linkc.225C>T p.Asp75Asp synonymous_variant 2/61 NM_000744.7 ENSP00000359285.4 P43681-1

Frequencies

GnomAD3 genomes
AF:
0.000466
AC:
71
AN:
152222
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.000235
Gnomad OTH
AF:
0.000958
GnomAD3 exomes
AF:
0.000164
AC:
41
AN:
249774
Hom.:
0
AF XY:
0.000147
AC XY:
20
AN XY:
135614
show subpopulations
Gnomad AFR exome
AF:
0.000808
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000222
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000149
AC:
218
AN:
1460316
Hom.:
0
Cov.:
38
AF XY:
0.000157
AC XY:
114
AN XY:
726446
show subpopulations
Gnomad4 AFR exome
AF:
0.00105
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000148
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000479
AC:
73
AN:
152340
Hom.:
0
Cov.:
34
AF XY:
0.000483
AC XY:
36
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.00125
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.000948
Alfa
AF:
0.000424
Hom.:
0
Bravo
AF:
0.000427
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000533

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 20, 2020- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsSep 07, 2017- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2022CHRNA4: BS1, BS2 -
Autosomal dominant nocturnal frontal lobe epilepsy Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 18, 2024- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 06, 2016This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.49
CADD
Benign
1.3
DANN
Benign
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs113080067; hg19: chr20-61990903; API