12-48771786-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate
The NM_015270.5(ADCY6):c.2975A>G(p.Tyr992Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,996 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 Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
ADCY6
NM_015270.5 missense
NM_015270.5 missense
Scores
12
3
2
Clinical Significance
Conservation
PhyloP100: 8.01
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 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, 0.886
PP5
?
Variant 12-48771786-T-C is Pathogenic according to our data. Variant chr12-48771786-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 243078.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADCY6 | NM_015270.5 | c.2975A>G | p.Tyr992Cys | missense_variant | 19/22 | ENST00000357869.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADCY6 | ENST00000357869.8 | c.2975A>G | p.Tyr992Cys | missense_variant | 19/22 | 2 | NM_015270.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727246
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Lethal congenital contracture syndrome 8 Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Aug 18, 2015 | Likely pathogenic based on conservation and prediction scores (Phylop, LRT, SIFT, Polyphen, MutationTaster). Identified in homozygous state in individual with congenital hypomyelinating neuropathy, congenital contractures, and vocal cord paralysis. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Nov 29, 2023 | The ADCY6 c.2975A>G (p.Tyr992Cys) variant has been reported in the homozygous state in one individual affected with arthrogryposis multiplex congenita with axoglial defects and foot deformities (Gonzaga-Jauregui C et al., PMID: 26257172). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by two submitters. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in the nucleotide cyclase domain, changes a polar tyrosine to a non-polar cysteine, and computational predictors indicate that the variant is damaging, evidence that correlates with impact to ADCY6 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variantis uncertain at this time. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 26, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
0.63
.;.;Gain of catalytic residue at E994 (P = 0.0019);
MVP
MPC
1.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at