rs786204798

Variant names:

• chr12-48768972-G-A
• rs786204798
• NM_015270.5:c.3346C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_015270.5(ADCY6):​c.3346C>T​(p.Arg1116Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ADCY6 NM_015270.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.19
• Publications: 4 publications found

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]

SPMIP11 (HGNC:48628): (sperm microtubule inner protein 11)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 12-48768972-G-A is Pathogenic according to our data. Variant chr12-48768972-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 189260.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015270.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY6	NM_015270.5	MANE Select	c.3346C>T	p.Arg1116Cys	missense	Exon 21 of 22	NP_056085.1	O43306-1
	ADCY6	NM_001390831.2		c.3346C>T	p.Arg1116Cys	missense	Exon 20 of 21	NP_001377760.1	O43306-1
	ADCY6	NM_001412819.1		c.3346C>T	p.Arg1116Cys	missense	Exon 21 of 22	NP_001399748.1	O43306-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY6	ENST00000357869.8	TSL:2 MANE Select	c.3346C>T	p.Arg1116Cys	missense	Exon 21 of 22	ENSP00000350536.4	O43306-1
	ADCY6	ENST00000307885.4	TSL:1	c.3346C>T	p.Arg1116Cys	missense	Exon 20 of 21	ENSP00000311405.4	O43306-1
	ADCY6	ENST00000960700.1		c.3427C>T	p.Arg1143Cys	missense	Exon 21 of 22	ENSP00000630759.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250878 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111960

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Lethal congenital contracture syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		4.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.78		Gain of catalytic residue at V1113 (P = 0)
MVP		0.83
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.87
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs786204798; hg19: chr12-49162755; COSMIC: COSV104606493; COSMIC: COSV104606493;