12-48771754-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_015270.5(ADCY6):c.3007G>A(p.Glu1003Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ADCY6 NM_015270.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.90

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ADCY6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant 12-48771754-C-T is Pathogenic according to our data. Variant chr12-48771754-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 995840.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY6	NM_015270.5	c.3007G>A	p.Glu1003Lys	missense_variant	19/22	ENST00000357869.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY6	ENST00000357869.8	c.3007G>A	p.Glu1003Lys	missense_variant	19/22	2	NM_015270.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lethal congenital contracture syndrome 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.94
MutPred		0.59		.;.;Gain of catalytic residue at L1005 (P = 0.0213);
MVP		0.79
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.86
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs1941551290; hg19: chr12-49165537;