Genetic Variant NM_183357.3:c.2176G>A (chr3-123319754-C-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.90

Publications

25 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
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

ADCY5 links:

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ACMG classification

Classification was made for transcript

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

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

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.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000428

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

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

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

2.9

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.85

MutPred

0.50

Gain of glycosylation at S728 (P = 0.0023)

MVP

0.86

MPC

1.2

ClinPred

1.0

GERP RS

5.1

Varity_R

0.94

gMVP

0.63

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over