chr8-130909797-G-C

Variant names:

• chr8-130909797-G-C
• rs369373540
• NM_001115.3:c.1551C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001115.3(ADCY8):​c.1551C>G​(p.Cys517Trp) variant causes a missense change involving the alteration of a non-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. Synonymous variant affecting the same amino acid position (i.e. C517C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY8 NM_001115.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 2 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY8	NM_001115.3	c.1551C>G	p.Cys517Trp	missense_variant	Exon 6 of 18	ENST00000286355.10	NP_001106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY8	ENST00000286355.10	c.1551C>G	p.Cys517Trp	missense_variant	Exon 6 of 18	1	NM_001115.3	ENSP00000286355.5
ADCY8	ENST00000377928.7	c.1551C>G	p.Cys517Trp	missense_variant	Exon 6 of 15	1		ENSP00000367161.3
ADCY8	ENST00000522949.1	c.396C>G	p.Cys132Trp	missense_variant	Exon 6 of 7	5		ENSP00000428010.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.89	D;D;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.1	H;.;.
PhyloP100		-0.066
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.88
MutPred		0.80		Gain of MoRF binding (P = 0.0094);Gain of MoRF binding (P = 0.0094);.;
MVP		0.81
MPC		1.5
ClinPred		1.0	D
GERP RS		-5.1
Varity_R		0.94
gMVP		0.95
Mutation Taster		=2/98	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: rs369373540; hg19: chr8-131922043;