chr3-123448117-AGCCGCCGCCGCCGAGCC-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_183357.3(ADCY5):c.412_428del(p.Gly138CysfsTer184) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000316 in 948,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000032 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ADCY5
NM_183357.3 frameshift
NM_183357.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.90
Genes affected
ADCY5 (HGNC:236): (adenylate cyclase 5) This gene encodes a member of the membrane-bound adenylyl cyclase enzymes. Adenylyl cyclases mediate G protein-coupled receptor signaling through the synthesis of the second messenger cAMP. Activity of the encoded protein is stimulated by the Gs alpha subunit of G protein-coupled receptors and is inhibited by protein kinase A, calcium and Gi alpha subunits. Single nucleotide polymorphisms in this gene may be associated with low birth weight and type 2 diabetes. Alternatively spliced transcript variants that encode different isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-123448117-AGCCGCCGCCGCCGAGCC-A is Pathogenic according to our data. Variant chr3-123448117-AGCCGCCGCCGCCGAGCC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817996.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADCY5 | NM_183357.3 | c.412_428del | p.Gly138CysfsTer184 | frameshift_variant | 1/21 | ENST00000462833.6 | |
ADCY5 | NM_001378259.1 | c.412_428del | p.Gly138CysfsTer184 | frameshift_variant | 1/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADCY5 | ENST00000462833.6 | c.412_428del | p.Gly138CysfsTer184 | frameshift_variant | 1/21 | 1 | NM_183357.3 | P1 | |
ADCY5 | ENST00000699718.1 | c.412_428del | p.Gly138CysfsTer184 | frameshift_variant | 1/22 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 146220Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 genomes
?
AF:
AC:
0
AN:
146220
Hom.:
Cov.:
32
FAILED QC
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000316 AC: 3AN: 948280Hom.: 0 AF XY: 0.00000444 AC XY: 2AN XY: 449958
GnomAD4 exome
AF:
AC:
3
AN:
948280
Hom.:
AF XY:
AC XY:
2
AN XY:
449958
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 146220Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 71126
GnomAD4 genome
?
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
146220
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
71126
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2019 | The c.412_428del17 variant in the ADCY5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Glycine 138, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 184 of the new reading frame, denoted p.Gly138CysfsX184. The c.412_428del17 variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.412_428del17 as a likely pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at