12-48775015-C-G

Variant names:

• chr12-48775015-C-G
• NM_015270.5:c.2020G>C

Variant summary

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

The NM_015270.5(ADCY6):​c.2020G>C​(p.Ala674Pro) variant causes a missense change. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A674S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY6 NM_015270.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.70

Genes affected

ADCY6 (HGNC:237): (adenylate cyclase 6) This gene encodes a member of the adenylyl cyclase family of proteins, which are required for the synthesis of cyclic AMP. All members of this family have an intracellular N-terminus, a tandem repeat of six transmembrane domains separated by a cytoplasmic loop, and a C-terminal cytoplasmic domain. The two cytoplasmic regions bind ATP and form the catalytic core of the protein. Adenylyl cyclases are important effectors of transmembrane signaling pathways and are regulated by the activity of G protein coupled receptor signaling. This protein belongs to a small subclass of adenylyl cyclase proteins that are functionally related and are inhibited by protein kinase A, calcium ions and nitric oxide. A mutation in this gene is associated with arthrogryposis multiplex congenita. [provided by RefSeq, May 2015]

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, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY6	NM_015270.5	c.2020G>C	p.Ala674Pro	missense_variant	Exon 12 of 22	ENST00000357869.8	NP_056085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY6	ENST00000357869.8	c.2020G>C	p.Ala674Pro	missense_variant	Exon 12 of 22	2	NM_015270.5	ENSP00000350536.4
ADCY6	ENST00000307885.4	c.2020G>C	p.Ala674Pro	missense_variant	Exon 11 of 21	1		ENSP00000311405.4
ADCY6	ENST00000550422.5	c.2020G>C	p.Ala674Pro	missense_variant	Exon 12 of 21	2		ENSP00000446730.1
ADCY6	ENST00000552090.1	n.542G>C		non_coding_transcript_exon_variant	Exon 6 of 8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.24
Sift	Benign	0.056	T;T;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.97	D;D;D
Vest4		0.86
MutPred		0.61		Gain of catalytic residue at C675 (P = 0);Gain of catalytic residue at C675 (P = 0);Gain of catalytic residue at C675 (P = 0);
MVP		0.50
MPC		1.2
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-49168798;