5-7757480-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_020546.3(ADCY2):c.1988T>C(p.Met663Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY2 NM_020546.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ADCY2
• BP4: Computational evidence support a benign effect (MetaRNN=0.28718257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY2	NM_020546.3	c.1988T>C	p.Met663Thr	missense_variant	16/25	ENST00000338316.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY2	ENST00000338316.9	c.1988T>C	p.Met663Thr	missense_variant	16/25	1	NM_020546.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.1988T>C (p.M663T) alteration is located in exon 16 (coding exon 16) of the ADCY2 gene. This alteration results from a T to C substitution at nucleotide position 1988, causing the methionine (M) at amino acid position 663 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	17
Dann	Benign	0.73
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.090
Sift	Benign	0.41	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.49
MutPred		0.67		Loss of stability (P = 0.04);
MVP		0.20
MPC		0.85
ClinPred		0.21	T
GERP RS		3.1
Varity_R		0.058
gMVP		0.68

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: chr5-7757593;