NM_183357.3:c.1252C>T

Variant names:

• chr3-123352464-G-A
• rs864309483
• NM_183357.3:c.1252C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_183357.3(ADCY5):​c.1252C>T​(p.Arg418Trp) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R418Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY5 NM_183357.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 4.40
• Publications: 34 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-123352463-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 218354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 3-123352464-G-A is Pathogenic according to our data. Variant chr3-123352464-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 162090.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.1252C>T	p.Arg418Trp	missense	Exon 2 of 21	NP_899200.1	O95622-1
	ADCY5	NM_001378259.1		c.1252C>T	p.Arg418Trp	missense	Exon 2 of 22	NP_001365188.1	A0A8V8TP58
	ADCY5	NM_001199642.1		c.202C>T	p.Arg68Trp	missense	Exon 2 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.1252C>T	p.Arg418Trp	missense	Exon 2 of 21	ENSP00000419361.1	O95622-1
	ADCY5	ENST00000850916.1		c.1414C>T	p.Arg472Trp	missense	Exon 2 of 21	ENSP00000520999.1	A0ABJ7H376
	ADCY5	ENST00000699718.1		c.1252C>T	p.Arg418Trp	missense	Exon 2 of 22	ENSP00000514543.1	A0A8V8TP58

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000552 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Dyskinesia with orofacial involvement, autosomal dominant (9)
7	-	-	not provided (7)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.64		Loss of disorder (P = 2e-04)
MVP		0.97
MPC		2.1
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.63
gMVP		0.86
Mutation Taster		=8/92	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: rs864309483; hg19: chr3-123071311; COSMIC: COSV100567383;