3-123448117-AGCCGCCGCCGCCGAGCCGCC-AGCC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_183357.3(ADCY5):c.412_428delGGCTCGGCGGCGGCGGC(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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.90

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

dyskinesia with orofacial involvement, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: G2P
neurodevelopmental disorder with hyperkinetic movements and dyskinesia
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial dyskinesia and facial myokymia
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
choreatic disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ADCY5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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 VariationId is 817996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY5	NM_183357.3 link	c.412_428delGGCTCGGCGGCGGCGGC	p.Gly138CysfsTer184	frameshift_variant	Exon 1 of 21	ENST00000462833.6	NP_899200.1
ADCY5	NM_001378259.1 link	c.412_428delGGCTCGGCGGCGGCGGC	p.Gly138CysfsTer184	frameshift_variant	Exon 1 of 22		NP_001365188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ADCY5	ENST00000462833.6 link	c.412_428delGGCTCGGCGGCGGCGGC	p.Gly138CysfsTer184	frameshift_variant	Exon 1 of 21	1	NM_183357.3	ENSP00000419361.1
ADCY5	ENST00000850916.1 link	c.574_590delGGCTCGGCGGCGGCGGC	p.Gly192CysfsTer184	frameshift_variant	Exon 1 of 21			ENSP00000520999.1
ADCY5	ENST00000699718.1 link	c.412_428delGGCTCGGCGGCGGCGGC	p.Gly138CysfsTer184	frameshift_variant	Exon 1 of 22			ENSP00000514543.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

146220

Hom.:

Cov.:

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

18244

American (AMR)

AF:

0.00

AC:

AN:

4288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8572

East Asian (EAS)

AF:

0.00

AC:

AN:

11230

South Asian (SAS)

AF:

0.00

AC:

AN:

19926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2176

European-Non Finnish (NFE)

AF:

0.00000358

AC:

AN:

838644

Other (OTH)

AF:

0.00

AC:

AN:

33988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000395253), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

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

African (AFR)

AF:

0.00

AC:

AN:

40598

American (AMR)

AF:

0.00

AC:

AN:

14750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

5052

South Asian (SAS)

AF:

0.00

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65858

Other (OTH)

AF:

0.00

AC:

AN:

2024

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Jan 24, 2019

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 29, 2022

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

PhyloP100

1.9

Mutation Taster

=39/161

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over