rs11168733

Positions:

• chr12-48776936-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015270.5(ADCY6):​c.1376+168C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 152,104 control chromosomes in the GnomAD database, including 1,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.11 (1501 hom., cov: 32)
• Consequence: ADCY6 NM_015270.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.709

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-48776936-G-A is Benign according to our data. Variant chr12-48776936-G-A is described in ClinVar as [Benign]. Clinvar id is 1225210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY6	NM_015270.5	c.1376+168C>T		intron_variant		ENST00000357869.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY6	ENST00000357869.8	c.1376+168C>T		intron_variant		2	NM_015270.5	P1
ADCY6	ENST00000307885.4	c.1376+168C>T		intron_variant		1		P1
ADCY6	ENST00000550422.5	c.1376+168C>T		intron_variant		2
ADCY6	ENST00000551435.1	n.618+168C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16653 AN: 151988 Hom.: 1494 Cov.: 32

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0639

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.0614

Gnomad FIN AF: 0.0397

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.0829

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.110 AC: 16683 AN: 152104 Hom.: 1501 Cov.: 32 AF XY: 0.106 AC XY: 7882 AN XY: 74344

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.0551

Gnomad4 ASJ AF: 0.0639

Gnomad4 EAS AF: 0.0249

Gnomad4 SAS AF: 0.0613

Gnomad4 FIN AF: 0.0397

Gnomad4 NFE AF: 0.0626

Gnomad4 OTH AF: 0.0820

Alfa AF: 0.0718 Hom.: 551

Bravo AF: 0.115

Asia WGS AF: 0.0480 AC: 166 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.2
DANN	Benign	0.53

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: rs11168733; hg19: chr12-49170719;