Variant 3-123448117-AGCCGCCGCCGCCGAGCCGCC-AGCC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000462833.6(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
ENST00000462833.6 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.90

Variant links:

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]

ADCY5 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY5	NM_183357.3 linkuse as main transcript	c.412_428del	p.Gly138CysfsTer184	frameshift_variant	1/21	ENST00000462833.6	NP_899200.1
ADCY5	NM_001378259.1 linkuse as main transcript	c.412_428del	p.Gly138CysfsTer184	frameshift_variant	1/22		NP_001365188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY5	ENST00000462833.6 linkuse as main transcript	c.412_428del	p.Gly138CysfsTer184	frameshift_variant	1/21	1	NM_183357.3	ENSP00000419361	P1	O95622-1
ADCY5	ENST00000699718.1 linkuse as main transcript	c.412_428del	p.Gly138CysfsTer184	frameshift_variant	1/22			ENSP00000514543

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

146220

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000316

AC:

AN:

948280

Hom.:

AF XY:

0.00000444

AC XY:

AN XY:

449958

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000358

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

146220

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71126

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Breakthrough Genomics, Breakthrough Genomics

Sep 29, 2022

This variant has not been reported in literature. However, truncating variants lying in the downstream of the identified variants have been reported as pathogenic in the context of dyskinesia with orofacial involvement, autosomal dominant/recessive in the ClinVar database. Loss-of-function variants in the ADCY5 gene are known to be pathogenic [PMID: 28971144, 34631954]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over