rs796065306

Variant names:

• chr3-123319754-C-T
• rs796065306
• NM_183357.3:c.2176G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_183357.3(ADCY5):​c.2176G>A​(p.Ala726Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADCY5 NM_183357.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.90
• Publications: 25 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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83
• PP5: Variant 3-123319754-C-T is Pathogenic according to our data. Variant chr3-123319754-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 162091.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.2176G>A	p.Ala726Thr	missense	Exon 10 of 21	NP_899200.1	O95622-1
	ADCY5	NM_001378259.1		c.2176G>A	p.Ala726Thr	missense	Exon 10 of 22	NP_001365188.1	A0A8V8TP58
	ADCY5	NM_001199642.1		c.1126G>A	p.Ala376Thr	missense	Exon 10 of 21	NP_001186571.1	O95622-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	ENST00000462833.6	TSL:1 MANE Select	c.2176G>A	p.Ala726Thr	missense	Exon 10 of 21	ENSP00000419361.1	O95622-1
	ADCY5	ENST00000850916.1		c.2338G>A	p.Ala780Thr	missense	Exon 10 of 21	ENSP00000520999.1	A0ABJ7H376
	ADCY5	ENST00000699718.1		c.2176G>A	p.Ala726Thr	missense	Exon 10 of 22	ENSP00000514543.1	A0A8V8TP58

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000428 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
2	-	-	Dyskinesia with orofacial involvement, autosomal dominant (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.50		Gain of glycosylation at S728 (P = 0.0023)
MVP		0.86
MPC		1.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.63
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs796065306; hg19: chr3-123038601;