2-24820741-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Strong BP6_Moderate

The NM_004036.5(ADCY3):c.3235G>A(p.Val1079Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,613,972 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: ADCY3 NM_004036.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.08

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ADCY3
• BP4: Computational evidence support a benign effect (MetaRNN=0.014249414).
• BP6: Variant 2-24820741-C-T is Benign according to our data. Variant chr2-24820741-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3044576.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY3	NM_004036.5	c.3235G>A	p.Val1079Ile	missense_variant	21/22	ENST00000679454.1
CENPO	NM_001322101.2	c.*1423C>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.3235G>A	p.Val1079Ile	missense_variant	21/22		NM_004036.5	P4
CENPO	ENST00000380834.7	c.*1423C>T		3_prime_UTR_variant	8/8	5	NM_001322101.2	P1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152138 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000808 AC: 203 AN: 251366 Hom.: 0 AF XY: 0.000854 AC XY: 116 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00119 AC: 1740 AN: 1461834 Hom.: 0 Cov.: 30 AF XY: 0.00114 AC XY: 828 AN XY: 727232

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152138 Hom.: 1 Cov.: 31 AF XY: 0.00113 AC XY: 84 AN XY: 74308

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00103

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000741 AC: 90

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ADCY3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.80	N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.95	N;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.11	T;.;.
Sift4G	Benign	0.079	T;T;T
Polyphen		0.96	D;.;.
Vest4		0.43
MVP		0.80
MPC		0.85
ClinPred		0.084	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.34

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: rs146553503; hg19: chr2-25043610; COSMIC: COSV99037410; COSMIC: COSV99037410;