3-123448117-AGCCGCCGCCGCCGAGCCGCC-AGCC

Variant names:

• chr3-123448117-AGCCGCCGCCGCCGAGCC-A
• rs1553751262
• NM_183357.3:c.412_428delGGCTCGGCGGCGGCGGC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.90
• Publications: 0 publications found

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

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• 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: Orphanet, Ambry Genetics
• choreatic disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183357.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	NM_183357.3	MANE Select	c.412_428delGGCTCGGCGGCGGCGGC	p.Gly138CysfsTer184	frameshift	Exon 1 of 21	NP_899200.1	O95622-1
	ADCY5	NM_001378259.1		c.412_428delGGCTCGGCGGCGGCGGC	p.Gly138CysfsTer184	frameshift	Exon 1 of 22	NP_001365188.1	A0A8V8TP58

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	ENST00000462833.6	TSL:1 MANE Select	c.412_428delGGCTCGGCGGCGGCGGC	p.Gly138CysfsTer184	frameshift	Exon 1 of 21	ENSP00000419361.1	O95622-1
	ADCY5	ENST00000850916.1		c.574_590delGGCTCGGCGGCGGCGGC	p.Gly192CysfsTer184	frameshift	Exon 1 of 21	ENSP00000520999.1	A0ABJ7H376
	ADCY5	ENST00000699718.1		c.412_428delGGCTCGGCGGCGGCGGC	p.Gly138CysfsTer184	frameshift	Exon 1 of 22	ENSP00000514543.1	A0A8V8TP58

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 146220 Hom.: 0 Cov.: 32

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

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

African (AFR) AF: 0.00 AC: 0 AN: 18244

American (AMR) AF: 0.00 AC: 0 AN: 4288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8572

East Asian (EAS) AF: 0.00 AC: 0 AN: 11230

South Asian (SAS) AF: 0.00 AC: 0 AN: 19926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2176

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 838644

Other (OTH) AF: 0.00 AC: 0 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.

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

African (AFR) AF: 0.00 AC: 0 AN: 40598

American (AMR) AF: 0.00 AC: 0 AN: 14750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 5052

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65858

Other (OTH) AF: 0.00 AC: 0 AN: 2024

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=39/161	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553751262; hg19: chr3-123166964;