8-130780690-C-A

Variant names:

• chr8-130780690-C-A
• rs771008212
• NM_001115.3:c.3456G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001115.3(ADCY8):​c.3456G>T​(p.Glu1152Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1152A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY8 NM_001115.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.72
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001115.3. 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
	ADCY8	NM_001115.3	MANE Select	c.3456G>T	p.Glu1152Asp	missense	Exon 18 of 18	NP_001106.1	P40145

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY8	ENST00000286355.10	TSL:1 MANE Select	c.3456G>T	p.Glu1152Asp	missense	Exon 18 of 18	ENSP00000286355.5	P40145
	ADCY8	ENST00000377928.7	TSL:1	c.3063G>T	p.Glu1021Asp	missense	Exon 15 of 15	ENSP00000367161.3	E7EVL1
	ADCY8	ENST00000912159.1		c.3366G>T	p.Glu1122Asp	missense	Exon 17 of 17	ENSP00000582218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.48
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.084	B
Vest4		0.83
MutPred		0.52		Loss of sheet (P = 0.1158)
MVP		0.88
MPC		0.38
ClinPred		0.76	D
GERP RS		4.9
Varity_R		0.15
gMVP		0.55
Mutation Taster		=36/64	disease causing

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: rs771008212; hg19: chr8-131792936;