12-48775065-G-C

Position:

• chr12-48775065-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_015270.5(ADCY6):​c.1981-11C>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001865
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.946

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 -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 id 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/exons	MANE	Protein	UniProt
ADCY6	NM_015270.5	c.1981-11C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000357869.8	NP_056085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY6	ENST00000357869.8	c.1981-11C>G		splice_polypyrimidine_tract_variant, intron_variant		2	NM_015270.5	ENSP00000350536	P1
ADCY6	ENST00000307885.4	c.1981-11C>G		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000311405	P1
ADCY6	ENST00000550422.5	c.1981-11C>G		splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000446730
ADCY6	ENST00000552090.1	n.503-11C>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.131 AC: 20891 AN: 159144 Hom.: 2074 AF XY: 0.125 AC XY: 10462 AN XY: 83514

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 SAS exome AF: 0.0956

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

Gnomad4 AFR exome AF: 0.455

Gnomad4 AMR exome AF: 0.0870

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.0148

Gnomad4 SAS exome AF: 0.0977

Gnomad4 FIN exome AF: 0.0928

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.158

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

Gnomad4 AFR AF: 0.451

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.0255

Gnomad4 SAS AF: 0.0981

Gnomad4 FIN AF: 0.0923

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.180

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

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	-0.28
CADD	Benign	22
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs3730070; hg19: chr12-49168848;