rs3730069

Positions:

• chr12-48775479-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015270.5(ADCY6):​c.1833-29A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,612,492 control chromosomes in the GnomAD database, including 18,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (5281 hom., cov: 32)
  • Exomes 𝑓: 0.12 (13301 hom.)
• Consequence: ADCY6 NM_015270.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.274

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-48775479-T-A is Benign according to our data. Variant chr12-48775479-T-A is described in ClinVar as [Benign]. Clinvar id is 1252860.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY6	NM_015270.5	c.1833-29A>T		intron_variant		ENST00000357869.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY6	ENST00000357869.8	c.1833-29A>T		intron_variant		2	NM_015270.5	P1
ADCY6	ENST00000307885.4	c.1833-29A>T		intron_variant		1		P1
ADCY6	ENST00000550422.5	c.1833-29A>T		intron_variant		2
ADCY6	ENST00000552090.1	n.355-29A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31349 AN: 151844 Hom.: 5269 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0255

Gnomad SAS AF: 0.0950

Gnomad FIN AF: 0.0780

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.116 AC: 28928 AN: 250308 Hom.: 3013 AF XY: 0.110 AC XY: 14810 AN XY: 135204

Gnomad AFR exome AF: 0.489

Gnomad AMR exome AF: 0.0608

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0275

Gnomad SAS exome AF: 0.0921

Gnomad FIN exome AF: 0.0761

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0981

GnomAD4 exome AF: 0.120 AC: 175611 AN: 1460530 Hom.: 13301 Cov.: 33 AF XY: 0.118 AC XY: 85863 AN XY: 726456

Gnomad4 AFR exome AF: 0.477

Gnomad4 AMR exome AF: 0.0675

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.0156

Gnomad4 SAS exome AF: 0.0938

Gnomad4 FIN exome AF: 0.0786

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.207 AC: 31391 AN: 151962 Hom.: 5281 Cov.: 32 AF XY: 0.199 AC XY: 14794 AN XY: 74282

Gnomad4 AFR AF: 0.470

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.0256

Gnomad4 SAS AF: 0.0951

Gnomad4 FIN AF: 0.0780

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.162

Alfa AF: 0.155 Hom.: 531

Bravo AF: 0.218

Asia WGS AF: 0.0770 AC: 267 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.79
CADD	Benign	15
DANN	Benign	0.77

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: rs3730069; hg19: chr12-49169262;