8-130783799-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001115.3(ADCY8):c.3160G>A(p.Glu1054Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADCY8 NM_001115.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36677033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY8	NM_001115.3	c.3160G>A	p.Glu1054Lys	missense_variant	17/18	ENST00000286355.10
ADCY8	XM_005250769.4	c.3070G>A	p.Glu1024Lys	missense_variant	16/17
ADCY8	XM_006716501.4	c.2962G>A	p.Glu988Lys	missense_variant	16/17
ADCY8	XM_017013006.2	c.2872G>A	p.Glu958Lys	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY8	ENST00000286355.10	c.3160G>A	p.Glu1054Lys	missense_variant	17/18	1	NM_001115.3	P1
ADCY8	ENST00000377928.7	c.2767G>A	p.Glu923Lys	missense_variant	14/15	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Mar 22, 2023

The c.3160G>A (p.E1054K) alteration is located in exon 17 (coding exon 17) of the ADCY8 gene. This alteration results from a G to A substitution at nucleotide position 3160, causing the glutamic acid (E) at amino acid position 1054 to be replaced by a lysine (K). 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	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.42	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.56	P;B
Vest4		0.55
MutPred		0.54		Gain of methylation at E1054 (P = 0.0028);.;
MVP		0.84
MPC		1.3
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.29
gMVP		0.64

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: chr8-131796045;