12-48769027-G-C

Variant names:

• chr12-48769027-G-C
• rs73296123
• NM_015270.5:c.3291C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015270.5(ADCY6):​c.3291C>G​(p.Ile1097Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY6 NM_015270.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.301

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY6	NM_015270.5	c.3291C>G	p.Ile1097Met	missense_variant	Exon 21 of 22	ENST00000357869.8	NP_056085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY6	ENST00000357869.8	c.3291C>G	p.Ile1097Met	missense_variant	Exon 21 of 22	2	NM_015270.5	ENSP00000350536.4
ADCY6	ENST00000307885.4	c.3291C>G	p.Ile1097Met	missense_variant	Exon 20 of 21	1		ENSP00000311405.4
ADCY6	ENST00000550422.5	c.3132C>G	p.Ile1044Met	missense_variant	Exon 20 of 21	2		ENSP00000446730.1
ADCY6	ENST00000547260.5	n.2145C>G		non_coding_transcript_exon_variant	Exon 6 of 7	2

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	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	.;.;D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.37	N
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.4	.;.;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.95
MutPred		0.65		.;.;Gain of catalytic residue at V1096 (P = 0);
MVP		0.63
MPC		1.3
ClinPred		1.0	D
GERP RS		-1.9
Varity_R		0.65
gMVP		0.90

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: rs73296123; hg19: chr12-49162810;