12-48775065-G-C

Variant names:

• chr12-48775065-G-C
• rs3730070
• NM_015270.5:c.1981-11C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_015270.5(ADCY6):​c.1981-11C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,551,208 control chromosomes in the GnomAD database, including 22,699 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5272 hom., cov: 31)
  • Exomes 𝑓: 0.15 (17427 hom.)
• Consequence: ADCY6 NM_015270.5 intron
• Scores: Splicing: ADA: 0.00001865
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.946
• Publications: 8 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 12-48775065-G-C is Benign according to our data. Variant chr12-48775065-G-C is described in ClinVar as Benign. ClinVar VariationId is 1226054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY6	NM_015270.5	c.1981-11C>G		intron_variant	Intron 11 of 21	ENST00000357869.8	NP_056085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY6	ENST00000357869.8	c.1981-11C>G		intron_variant	Intron 11 of 21	2	NM_015270.5	ENSP00000350536.4
ADCY6	ENST00000307885.4	c.1981-11C>G		intron_variant	Intron 10 of 20	1		ENSP00000311405.4
ADCY6	ENST00000550422.5	c.1981-11C>G		intron_variant	Intron 11 of 20	2		ENSP00000446730.1
ADCY6	ENST00000552090.1	n.503-11C>G		intron_variant	Intron 5 of 7	5

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33314 AN: 151904 Hom.: 5263 Cov.: 31

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.0981

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.131 AC: 20891 AN: 159144 AF XY: 0.125

Gnomad AFR exome AF: 0.468

Gnomad AMR exome AF: 0.0787

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.0268

Gnomad FIN exome AF: 0.0885

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.147 AC: 206169 AN: 1399186 Hom.: 17427 Cov.: 32 AF XY: 0.145 AC XY: 99935 AN XY: 690286

African (AFR) AF: 0.455 AC: 14389 AN: 31634

American (AMR) AF: 0.0870 AC: 3110 AN: 35766

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3789 AN: 25170

East Asian (EAS) AF: 0.0148 AC: 530 AN: 35876

South Asian (SAS) AF: 0.0977 AC: 7741 AN: 79250

European-Finnish (FIN) AF: 0.0928 AC: 4598 AN: 49544

Middle Eastern (MID) AF: 0.109 AC: 621 AN: 5682

European-Non Finnish (NFE) AF: 0.150 AC: 162244 AN: 1078208

Other (OTH) AF: 0.158 AC: 9147 AN: 58056

GnomAD4 genome AF: 0.219 AC: 33349 AN: 152022 Hom.: 5272 Cov.: 31 AF XY: 0.211 AC XY: 15710 AN XY: 74348

African (AFR) AF: 0.451 AC: 18651 AN: 41386

American (AMR) AF: 0.131 AC: 2002 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 518 AN: 3470

East Asian (EAS) AF: 0.0255 AC: 132 AN: 5180

South Asian (SAS) AF: 0.0981 AC: 473 AN: 4820

European-Finnish (FIN) AF: 0.0923 AC: 979 AN: 10606

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10006 AN: 67964

Other (OTH) AF: 0.180 AC: 380 AN: 2112

Alfa AF: 0.119 Hom.: 301

Bravo AF: 0.231

Asia WGS AF: 0.0770 AC: 270 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.66
PhyloP100		0.95
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3730070; hg19: chr12-49168848;