12-48769027-G-A

Position:

• chr12-48769027-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015270.5(ADCY6):​c.3291C>T​(p.Ile1097=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,612,836 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (41 hom.)
• Consequence: ADCY6 NM_015270.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.301

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]

TEX49 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-48769027-G-A is Benign according to our data. Variant chr12-48769027-G-A is described in ClinVar as [Benign]. Clinvar id is 788579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.301 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2035/152202) while in subpopulation AFR AF= 0.0459 (1905/41508). AF 95% confidence interval is 0.0442. There are 48 homozygotes in gnomad4. There are 926 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY6	NM_015270.5	c.3291C>T	p.Ile1097=	synonymous_variant	21/22	ENST00000357869.8	NP_056085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY6	ENST00000357869.8	c.3291C>T	p.Ile1097=	synonymous_variant	21/22	2	NM_015270.5	ENSP00000350536	P1
ADCY6	ENST00000307885.4	c.3291C>T	p.Ile1097=	synonymous_variant	20/21	1		ENSP00000311405	P1
ADCY6	ENST00000550422.5	c.3132C>T	p.Ile1044=	synonymous_variant	20/21	2		ENSP00000446730
ADCY6	ENST00000547260.5	n.2145C>T		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2033 AN: 152084 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00362 AC: 906 AN: 250180 Hom.: 23 AF XY: 0.00248 AC XY: 336 AN XY: 135362

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000873

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.00130 AC: 1906 AN: 1460634 Hom.: 41 Cov.: 32 AF XY: 0.00111 AC XY: 808 AN XY: 726598

Gnomad4 AFR exome AF: 0.0461

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000404

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.0134 AC: 2035 AN: 152202 Hom.: 48 Cov.: 32 AF XY: 0.0124 AC XY: 926 AN XY: 74410

Gnomad4 AFR AF: 0.0459

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00560 Hom.: 13

Bravo AF: 0.0149

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.000119

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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.7
DANN	Benign	0.84

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: rs73296123; hg19: chr12-49162810;