Genetic Variant ADCY2:p.Pro27Gln (chr5-7396376-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_020546.3(ADCY2):c.80C>A(p.Pro27Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,407,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ADCY2
NM_020546.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.372

Publications

1 publications found

Variant links:

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]

ADCY2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10253164).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020546.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY2	NM_020546.3	MANE Select	c.80C>A	p.Pro27Gln	missense	Exon 1 of 25	NP_065433.2	Q08462-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADCY2	ENST00000338316.9	TSL:1 MANE Select	c.80C>A	p.Pro27Gln	missense	Exon 1 of 25	ENSP00000342952.4	Q08462-1
ADCY2	ENST00000915366.1		c.80C>A	p.Pro27Gln	missense	Exon 1 of 25	ENSP00000585425.1
ADCY2	ENST00000915369.1		c.80C>A	p.Pro27Gln	missense	Exon 1 of 24	ENSP00000585428.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000355

AC:

AN:

1407508

Hom.:

Cov.:

AF XY:

0.00000429

AC XY:

AN XY:

699734

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29044

American (AMR)

AF:

0.00

AC:

AN:

38940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24512

East Asian (EAS)

AF:

0.00

AC:

AN:

33090

South Asian (SAS)

AF:

0.00

AC:

AN:

81742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5244

European-Non Finnish (NFE)

AF:

0.00000460

AC:

AN:

1086036

Other (OTH)

AF:

0.00

AC:

AN:

57698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000333

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.7

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.26

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.32

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.14

PhyloP100

-0.37

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.10

REVEL

Benign

0.13

Sift

Benign

0.13

Sift4G

Benign

0.19

Polyphen

0.0030

Vest4

0.14

MVP

0.31

MPC

0.68

ClinPred

0.11

GERP RS

-0.63

PromoterAI

-0.046

Neutral

(source)

Varity_R

0.041

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over