rs3730069

Variant names:

• chr12-48775479-T-A
• rs3730069
• NM_015270.5:c.1833-29A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-48775479-T-A
• chr12-48775479-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.274
• Publications: 6 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]

ADCY6 Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 8

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypomyelination neuropathy-arthrogryposis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1252860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY6	NM_015270.5	MANE Select	c.1833-29A>T		intron	N/A	NP_056085.1
	ADCY6	NM_001390831.2		c.1833-29A>T		intron	N/A	NP_001377760.1
	ADCY6	NM_001412819.1		c.1833-29A>T		intron	N/A	NP_001399748.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY6	ENST00000357869.8	TSL:2 MANE Select	c.1833-29A>T		intron	N/A	ENSP00000350536.4
	ADCY6	ENST00000307885.4	TSL:1	c.1833-29A>T		intron	N/A	ENSP00000311405.4
	ADCY6	ENST00000550422.5	TSL:2	c.1833-29A>T		intron	N/A	ENSP00000446730.1

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

GnomAD2 exomes AF: 0.116 AC: 28928 AN: 250308 AF XY: 0.110

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 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

African (AFR) AF: 0.477 AC: 15948 AN: 33432

American (AMR) AF: 0.0675 AC: 3016 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2695 AN: 26106

East Asian (EAS) AF: 0.0156 AC: 619 AN: 39674

South Asian (SAS) AF: 0.0938 AC: 8082 AN: 86124

European-Finnish (FIN) AF: 0.0786 AC: 4193 AN: 53336

Middle Eastern (MID) AF: 0.0974 AC: 561 AN: 5758

European-Non Finnish (NFE) AF: 0.119 AC: 132502 AN: 1111106

Other (OTH) AF: 0.133 AC: 7995 AN: 60324

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

African (AFR) AF: 0.470 AC: 19463 AN: 41380

American (AMR) AF: 0.112 AC: 1706 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 363 AN: 3466

East Asian (EAS) AF: 0.0256 AC: 132 AN: 5160

South Asian (SAS) AF: 0.0951 AC: 458 AN: 4818

European-Finnish (FIN) AF: 0.0780 AC: 825 AN: 10576

Middle Eastern (MID) AF: 0.0890 AC: 26 AN: 292

European-Non Finnish (NFE) AF: 0.117 AC: 7945 AN: 67970

Other (OTH) AF: 0.162 AC: 342 AN: 2108

Alfa AF: 0.155 Hom.: 531

Bravo AF: 0.218

Asia WGS AF: 0.0770 AC: 267 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.77
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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: rs3730069; hg19: chr12-49169262;