rs11676272

Positions:

• chr2-24918669-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_004036.5(ADCY3):​c.319T>C​(p.Ser107Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,613,848 control chromosomes in the GnomAD database, including 200,579 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.56 (26559 hom., cov: 32)
  • Exomes 𝑓: 0.48 (174020 hom.)
• Consequence: ADCY3 NM_004036.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• 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=3.1551988E-6).
• BP6: Variant 2-24918669-A-G is Benign according to our data. Variant chr2-24918669-A-G is described in ClinVar as [Benign]. Clinvar id is 1541304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY3	NM_004036.5	c.319T>C	p.Ser107Pro	missense_variant	2/22	ENST00000679454.1	NP_004027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY3	ENST00000679454.1	c.319T>C	p.Ser107Pro	missense_variant	2/22		NM_004036.5	ENSP00000505261	P4

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85224 AN: 151980 Hom.: 26498 Cov.: 32

Gnomad AFR AF: 0.847

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.529

GnomAD3 exomes AF: 0.466 AC: 117121 AN: 251328 Hom.: 29246 AF XY: 0.464 AC XY: 63060 AN XY: 135852

Gnomad AFR exome AF: 0.856

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.403

Gnomad EAS exome AF: 0.431

Gnomad SAS exome AF: 0.484

Gnomad FIN exome AF: 0.428

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.452

GnomAD4 exome AF: 0.482 AC: 704605 AN: 1461750 Hom.: 174020 Cov.: 75 AF XY: 0.481 AC XY: 349755 AN XY: 727174

Gnomad4 AFR exome AF: 0.867

Gnomad4 AMR exome AF: 0.326

Gnomad4 ASJ exome AF: 0.401

Gnomad4 EAS exome AF: 0.451

Gnomad4 SAS exome AF: 0.482

Gnomad4 FIN exome AF: 0.420

Gnomad4 NFE exome AF: 0.482

Gnomad4 OTH exome AF: 0.492

GnomAD4 genome AF: 0.561 AC: 85338 AN: 152098 Hom.: 26559 Cov.: 32 AF XY: 0.551 AC XY: 40961 AN XY: 74350

Gnomad4 AFR AF: 0.847

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.426

Gnomad4 SAS AF: 0.484

Gnomad4 FIN AF: 0.402

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.523

Alfa AF: 0.484 Hom.: 31554

Bravo AF: 0.571

TwinsUK AF: 0.491 AC: 1822

ALSPAC AF: 0.476 AC: 1834

ESP6500AA AF: 0.840 AC: 3701

ESP6500EA AF: 0.472 AC: 4059

ExAC AF: 0.479 AC: 58212

Asia WGS AF: 0.453 AC: 1577 AN: 3478

EpiCase AF: 0.465

EpiControl AF: 0.468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	14
DANN	Benign	0.089
DEOGEN2	Benign	0.26	T;.;.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.048	T;T;T;T
MetaRNN	Benign	0.0000032	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;.;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.42	N;.;N;N
REVEL	Benign	0.21
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	0.23	T;T;.;T
Polyphen		0.0	B;.;.;.
Vest4		0.052
MPC		0.60
ClinPred		0.00049	T
GERP RS		2.9
Varity_R		0.10
gMVP		0.83

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: rs11676272; hg19: chr2-25141538; COSMIC: COSV53167752;