rs11676272

Variant names:

• chr2-24918669-A-G
• rs11676272
• NM_004036.5:c.319T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 116 publications found

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]

ADCY3 Gene-Disease associations (from GenCC):

• body mass index quantitative trait locus 19

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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 rank	MANE	Protein	UniProt
ADCY3	NM_004036.5	c.319T>C	p.Ser107Pro	missense_variant	Exon 2 of 22	ENST00000679454.1	NP_004027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY3	ENST00000679454.1	c.319T>C	p.Ser107Pro	missense_variant	Exon 2 of 22		NM_004036.5	ENSP00000505261.1

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

GnomAD2 exomes AF: 0.466 AC: 117121 AN: 251328 AF XY: 0.464

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 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

African (AFR) AF: 0.867 AC: 29034 AN: 33478

American (AMR) AF: 0.326 AC: 14580 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 10474 AN: 26136

East Asian (EAS) AF: 0.451 AC: 17908 AN: 39696

South Asian (SAS) AF: 0.482 AC: 41576 AN: 86258

European-Finnish (FIN) AF: 0.420 AC: 22402 AN: 53336

Middle Eastern (MID) AF: 0.432 AC: 2490 AN: 5768

European-Non Finnish (NFE) AF: 0.482 AC: 536415 AN: 1111962

Other (OTH) AF: 0.492 AC: 29726 AN: 60394

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

African (AFR) AF: 0.847 AC: 35195 AN: 41542

American (AMR) AF: 0.404 AC: 6173 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1411 AN: 3472

East Asian (EAS) AF: 0.426 AC: 2204 AN: 5170

South Asian (SAS) AF: 0.484 AC: 2330 AN: 4818

European-Finnish (FIN) AF: 0.402 AC: 4257 AN: 10584

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32208 AN: 67926

Other (OTH) AF: 0.523 AC: 1107 AN: 2116

Alfa AF: 0.498 Hom.: 80364

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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;.;.;.
PhyloP100		1.3
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
PromoterAI		-0.015	Neutral
Varity_R		0.10
gMVP		0.83
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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