12-48771042-T-C

Position:

• chr12-48771042-T-C

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.3052-72A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,476,018 control chromosomes in the GnomAD database, including 15,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1703 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13720 hom.)
• Consequence: ADCY6 NM_015270.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.26

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]

TEX49 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-48771042-T-C is Benign according to our data. Variant chr12-48771042-T-C is described in ClinVar as [Benign]. Clinvar id is 1283688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY6	NM_015270.5	c.3052-72A>G		intron_variant		ENST00000357869.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY6	ENST00000357869.8	c.3052-72A>G		intron_variant		2	NM_015270.5	P1
ADCY6	ENST00000307885.4	c.3052-72A>G		intron_variant		1		P1
ADCY6	ENST00000550422.5	c.2893-72A>G		intron_variant		2
ADCY6	ENST00000547260.5	n.1834A>G		non_coding_transcript_exon_variant	5/7	2

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22121 AN: 152042 Hom.: 1701 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.0974

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0255

Gnomad SAS AF: 0.0976

Gnomad FIN AF: 0.0928

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.124

GnomAD4 exome AF: 0.141 AC: 186046 AN: 1323858 Hom.: 13720 Cov.: 20 AF XY: 0.139 AC XY: 91207 AN XY: 655406

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.0689

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.0151

Gnomad4 SAS exome AF: 0.0985

Gnomad4 FIN exome AF: 0.0946

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.145 AC: 22129 AN: 152160 Hom.: 1703 Cov.: 32 AF XY: 0.140 AC XY: 10401 AN XY: 74402

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.0972

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.0255

Gnomad4 SAS AF: 0.0977

Gnomad4 FIN AF: 0.0928

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.123

Alfa AF: 0.156 Hom.: 495

Bravo AF: 0.147

Asia WGS AF: 0.0590 AC: 205 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	-0.90
CADD	Benign	0.67
DANN	Benign	0.68

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: rs9804777; hg19: chr12-49164825;