8-130836419-C-T

Position:

• chr8-130836419-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001115.3(ADCY8):​c.2533G>A​(p.Val845Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY8 NM_001115.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY8	NM_001115.3	c.2533G>A	p.Val845Met	missense_variant	12/18	ENST00000286355.10	NP_001106.1
ADCY8	XM_005250769.4	c.2443G>A	p.Val815Met	missense_variant	11/17		XP_005250826.1
ADCY8	XM_006716501.4	c.2335G>A	p.Val779Met	missense_variant	11/17		XP_006716564.1
ADCY8	XM_017013006.2	c.2245G>A	p.Val749Met	missense_variant	10/16		XP_016868495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY8	ENST00000286355.10	c.2533G>A	p.Val845Met	missense_variant	12/18	1	NM_001115.3	ENSP00000286355.5
ADCY8	ENST00000377928.7	c.2140G>A	p.Val714Met	missense_variant	9/15	1		ENSP00000367161.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2024

The c.2533G>A (p.V845M) alteration is located in exon 12 (coding exon 12) of the ADCY8 gene. This alteration results from a G to A substitution at nucleotide position 2533, causing the valine (V) at amino acid position 845 to be replaced by a methionine (M). 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	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0070	D;T
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.41		Gain of helix (P = 0.2294);.;
MVP		0.92
MPC		1.3
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.28
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-131848665;