5-7709298-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_020546.3(ADCY2):c.1489T>A(p.Tyr497Asn) 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 Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADCY2 NM_020546.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.74

Genes affected

ADCY2 (HGNC:233): (adenylate cyclase 2) This gene encodes a member of the family of adenylate cyclases, which are membrane-associated enzymes that catalyze the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). This enzyme is insensitive to Ca(2+)/calmodulin, and is stimulated by the G protein beta and gamma subunit complex. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ADCY2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY2	NM_020546.3	c.1489T>A	p.Tyr497Asn	missense_variant	10/25	ENST00000338316.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY2	ENST00000338316.9	c.1489T>A	p.Tyr497Asn	missense_variant	10/25	1	NM_020546.3	P1
	ENST00000514105.2	n.163-1137A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

ADCY2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Undiagnosed Diseases Network, NIH

Dec 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.022	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.062	T
Polyphen		0.93	P
Vest4		0.90
MutPred		0.62		Gain of disorder (P = 0.011);
MVP		0.92
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.89
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-7709411;