Variant 8-130780614-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001115.3(ADCY8):c.3532C>G(p.Pro1178Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ADCY8
NM_001115.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.80

Variant links:

Genes affected

ADCY8 (HGNC:239): (adenylate cyclase 8) Adenylate cyclase is a membrane bound enzyme that catalyses the formation of cyclic AMP from ATP. The enzymatic activity is under the control of several hormones, and different polypeptides participate in the transduction of the signal from the receptor to the catalytic moiety. Stimulatory or inhibitory receptors (Rs and Ri) interact with G proteins (Gs and Gi) that exhibit GTPase activity and they modulate the activity of the catalytic subunit of the adenylyl cyclase [provided by RefSeq, Jul 2008]

ADCY8 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY8	NM_001115.3 linkuse as main transcript	c.3532C>G	p.Pro1178Ala	missense_variant	18/18	ENST00000286355.10	NP_001106.1	P40145A0A0K0K1K3Q4F7X0
ADCY8	XM_005250769.4 linkuse as main transcript	c.3442C>G	p.Pro1148Ala	missense_variant	17/17		XP_005250826.1
ADCY8	XM_006716501.4 linkuse as main transcript	c.3334C>G	p.Pro1112Ala	missense_variant	17/17		XP_006716564.1
ADCY8	XM_017013006.2 linkuse as main transcript	c.3244C>G	p.Pro1082Ala	missense_variant	16/16		XP_016868495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY8	ENST00000286355.10 linkuse as main transcript	c.3532C>G	p.Pro1178Ala	missense_variant	18/18	1	NM_001115.3	ENSP00000286355.5		P40145
ADCY8	ENST00000377928.7 linkuse as main transcript	c.3139C>G	p.Pro1047Ala	missense_variant	15/15	1		ENSP00000367161.3		E7EVL1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251074

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.3532C>G (p.P1178A) alteration is located in exon 18 (coding exon 18) of the ADCY8 gene. This alteration results from a C to G substitution at nucleotide position 3532, causing the proline (P) at amino acid position 1178 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

0.054

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;T

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.41

N;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.92

N;N

REVEL

Benign

0.23

Sift

Benign

0.46

T;T

Sift4G

Benign

0.82

T;T

Polyphen

0.025

B;B

Vest4

0.67

MutPred

0.43

Gain of sheet (P = 0.1945);.;

MVP

0.85

MPC

0.40

ClinPred

0.15

GERP RS

5.8

Varity_R

0.11

gMVP

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over