12-48771786-T-C

Position:

• chr12-48771786-T-C

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.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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ADCY6 NM_015270.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADCY6. . Gene score misZ 2.6826 (greater than the threshold 3.09). Trascript score misZ 3.621 (greater than threshold 3.09). GenCC has associacion of gene with lethal congenital contracture syndrome 8, hypomyelination neuropathy-arthrogryposis syndrome.
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 243078.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY6	NM_015270.5	c.2975A>G	p.Tyr992Cys	missense_variant	19/22	ENST00000357869.8	NP_056085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY6	ENST00000357869.8	c.2975A>G	p.Tyr992Cys	missense_variant	19/22	2	NM_015270.5	ENSP00000350536	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lethal congenital contracture syndrome 8 Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 26, 2021	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	.;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.6	D;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.94
MutPred		0.63		.;.;Gain of catalytic residue at E994 (P = 0.0019);
MVP		0.64
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.85
gMVP		0.85

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: rs879253864; hg19: chr12-49165569;