3-123448117-AGCCGCCGCCGCCGAGCCGCC-AGCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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: 0 AN: 146220 Hom.: 0 Cov.: 32 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: 3 AN: 948280 Hom.: 0 AF XY: 0.00000444 AC XY: 2 AN XY: 449958

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: 0 AN: 146220 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 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:1

Revision: criteria provided, single submitter

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: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553751262; hg19: chr3-123166964;