chr2-24820071-C-T

Position:

• chr2-24820071-C-T

Variant summary

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

The NM_004036.5(ADCY3):​c.3296G>A​(p.Arg1099His) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 1,573,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ADCY3 NM_004036.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.00

Genes affected

ADCY3 (HGNC:234): (adenylate cyclase 3) This gene encodes adenylyl cyclase 3 which is a membrane-associated enzyme and catalyzes the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). This protein appears to be widely expressed in various human tissues and may be involved in a number of physiological and pathophysiological metabolic processes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

CENPO (HGNC:28152): (centromere protein O) This gene encodes a component of the interphase centromere complex. The encoded protein is localized to the centromere throughout the cell cycle and is required for bipolar spindle assembly, chromosome segregation and checkpoint signaling during mitosis. Alternatively spliced transcript variants encoding multiple protein isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADCY3. . Gene score misZ 2.5726 (greater than the threshold 3.09). Trascript score misZ 3.1828 (greater than threshold 3.09). GenCC has associacion of gene with body mass index quantitative trait locus 19.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36613238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY3	NM_004036.5	c.3296G>A	p.Arg1099His	missense_variant	22/22	ENST00000679454.1
CENPO	NM_001322101.2	c.*753C>T		3_prime_UTR_variant	8/8	ENST00000380834.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY3	ENST00000679454.1	c.3296G>A	p.Arg1099His	missense_variant	22/22		NM_004036.5	P4
CENPO	ENST00000380834.7	c.*753C>T		3_prime_UTR_variant	8/8	5	NM_001322101.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 150864 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000636 AC: 14 AN: 220290 Hom.: 0 AF XY: 0.0000752 AC XY: 9 AN XY: 119632

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000371

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000183 AC: 26 AN: 1422376 Hom.: 0 Cov.: 32 AF XY: 0.0000198 AC XY: 14 AN XY: 705874

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.000303

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000101

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 150864 Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2 AN XY: 73606

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

ADCY3-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2024

The ADCY3 c.3299G>A variant is predicted to result in the amino acid substitution p.Arg1100His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.039% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.0030	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;.
Eigen	Benign	-0.012
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.49	N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N;.;.
REVEL	Uncertain	0.48
Sift	Benign	0.15	T;.;.
Sift4G	Benign	0.16	T;T;T
Polyphen		0.15	B;.;.
Vest4		0.49
MutPred		0.64		Loss of MoRF binding (P = 0.0076);.;.;
MVP		0.78
MPC		0.50
ClinPred		0.11	T
GERP RS		5.3
Varity_R		0.23
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs775633915; hg19: chr2-25042940;