rs3730071

Positions:

chr12-48775015-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_015270.5(ADCY6):c.2020G>T(p.Ala674Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0245 in 1,558,114 control chromosomes in the GnomAD database, including 546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.017 ( 25 hom., cov: 32)

Exomes 𝑓: 0.025 ( 521 hom. )

Consequence

ADCY6
NM_015270.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.70

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADCY6. . Gene score misZ 2.6826 (greater than the threshold 3.09). Trascript score misZ 3.621 (greater than threshold 3.09). GenCC has associacion of gene with lethal congenital contracture syndrome 8, hypomyelination neuropathy-arthrogryposis syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.009392977).

BP6

Variant 12-48775015-C-A is Benign according to our data. Variant chr12-48775015-C-A is described in ClinVar as [Benign]. Clinvar id is 3055951.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2603/152168) while in subpopulation NFE AF= 0.0283 (1923/67980). AF 95% confidence interval is 0.0272. There are 25 homozygotes in gnomad4. There are 1155 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY6	NM_015270.5 linkuse as main transcript	c.2020G>T	p.Ala674Ser	missense_variant	12/22	ENST00000357869.8	NP_056085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY6	ENST00000357869.8 linkuse as main transcript	c.2020G>T	p.Ala674Ser	missense_variant	12/22	2	NM_015270.5	ENSP00000350536	P1	O43306-1
ADCY6	ENST00000307885.4 linkuse as main transcript	c.2020G>T	p.Ala674Ser	missense_variant	11/21	1		ENSP00000311405	P1	O43306-1
ADCY6	ENST00000550422.5 linkuse as main transcript	c.2020G>T	p.Ala674Ser	missense_variant	12/21	2		ENSP00000446730		O43306-2
ADCY6	ENST00000552090.1 linkuse as main transcript	n.542G>T		non_coding_transcript_exon_variant	6/8	5

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2606

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00503

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.0383

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00886

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0283

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0164

AC:

2727

AN:

166566

Hom.:

AF XY:

0.0159

AC XY:

1393

AN XY:

87672

show subpopulations

Gnomad AFR exome

AF:

0.00538

Gnomad AMR exome

AF:

0.00745

Gnomad ASJ exome

AF:

0.0381

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00290

Gnomad FIN exome

AF:

0.00731

Gnomad NFE exome

AF:

0.0279

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.0253

AC:

35594

AN:

1405946

Hom.:

521

Cov.:

AF XY:

0.0244

AC XY:

16956

AN XY:

694092

show subpopulations

Gnomad4 AFR exome

AF:

0.00472

Gnomad4 AMR exome

AF:

0.00894

Gnomad4 ASJ exome

AF:

0.0401

Gnomad4 EAS exome

AF:

0.0000275

Gnomad4 SAS exome

AF:

0.00290

Gnomad4 FIN exome

AF:

0.00872

Gnomad4 NFE exome

AF:

0.0295

Gnomad4 OTH exome

AF:

0.0227

GnomAD4 genome

AF:

0.0171

AC:

2603

AN:

152168

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1155

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00499

Gnomad4 AMR

AF:

0.0126

Gnomad4 ASJ

AF:

0.0383

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00886

Gnomad4 NFE

AF:

0.0283

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0278

Hom.:

Bravo

AF:

0.0179

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0304

AC:

117

ESP6500AA

AF:

0.00596

AC:

ESP6500EA

AF:

0.0303

AC:

259

ExAC

AF:

0.00838

AC:

956

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ADCY6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

.;.;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;.;D

MetaRNN

Benign

0.0094

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.72

P;P;B

Vest4

0.51

MPC

0.61

ClinPred

0.020

GERP RS

3.7

Varity_R

0.24

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over