chr12-48776936-G-A

Variant names:

• chr12-48776936-G-A
• rs11168733
• NM_015270.5:c.1376+168C>T

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.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
• Publications: 1 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=-0.94).
• BP6: Variant 12-48776936-G-A is Benign according to our data. Variant chr12-48776936-G-A is described in ClinVar as Benign. ClinVar VariationId 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.

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.1376+168C>T		intron	N/A	NP_056085.1
	ADCY6	NM_001390831.2		c.1376+168C>T		intron	N/A	NP_001377760.1
	ADCY6	NM_001412819.1		c.1376+168C>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.1376+168C>T		intron	N/A	ENSP00000350536.4
	ADCY6	ENST00000307885.4	TSL:1	c.1376+168C>T		intron	N/A	ENSP00000311405.4
	ADCY6	ENST00000550422.5	TSL:2	c.1376+168C>T		intron	N/A	ENSP00000446730.1

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

African (AFR) AF: 0.248 AC: 10293 AN: 41470

American (AMR) AF: 0.0551 AC: 843 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 222 AN: 3472

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5180

South Asian (SAS) AF: 0.0613 AC: 296 AN: 4830

European-Finnish (FIN) AF: 0.0397 AC: 420 AN: 10592

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0626 AC: 4252 AN: 67962

Other (OTH) AF: 0.0820 AC: 173 AN: 2110

Alfa AF: 0.0739 Hom.: 1560

Bravo AF: 0.115

Asia WGS AF: 0.0480 AC: 166 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	-0.94
CADD	Benign	2.2
DANN	Benign	0.53
PhyloP100		-0.71
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: rs11168733; hg19: chr12-49170719;