Genetic Variant ADCY6:p.Ala674Ser (chr12-48775015-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_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).

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

Publications

29 publications found

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 Gene-Disease associations (from GenCC):

lethal congenital contracture syndrome 8
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hypomyelination neuropathy-arthrogryposis syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ADCY6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADCY6	NM_015270.5	MANE Select	c.2020G>T	p.Ala674Ser	missense	Exon 12 of 22	NP_056085.1	O43306-1
ADCY6	NM_001390831.2		c.2020G>T	p.Ala674Ser	missense	Exon 11 of 21	NP_001377760.1	O43306-1
ADCY6	NM_001412819.1		c.2020G>T	p.Ala674Ser	missense	Exon 12 of 22	NP_001399748.1	O43306-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADCY6	ENST00000357869.8	TSL:2 MANE Select	c.2020G>T	p.Ala674Ser	missense	Exon 12 of 22	ENSP00000350536.4	O43306-1
ADCY6	ENST00000307885.4	TSL:1	c.2020G>T	p.Ala674Ser	missense	Exon 11 of 21	ENSP00000311405.4	O43306-1
ADCY6	ENST00000960700.1		c.2101G>T	p.Ala701Ser	missense	Exon 12 of 22	ENSP00000630759.1

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

GnomAD2 exomes

AF:

0.0164

AC:

2727

AN:

166566

AF XY:

0.0159

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 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

African (AFR)

AF:

0.00472

AC:

151

AN:

31964

American (AMR)

AF:

0.00894

AC:

324

AN:

36256

Ashkenazi Jewish (ASJ)

AF:

0.0401

AC:

1011

AN:

25224

East Asian (EAS)

AF:

0.0000275

AC:

AN:

36408

South Asian (SAS)

AF:

0.00290

AC:

231

AN:

79586

European-Finnish (FIN)

AF:

0.00872

AC:

435

AN:

49898

Middle Eastern (MID)

AF:

0.0329

AC:

188

AN:

5714

European-Non Finnish (NFE)

AF:

0.0295

AC:

31930

AN:

1082556

Other (OTH)

AF:

0.0227

AC:

1323

AN:

58340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1789

3578

5368

7157

8946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1226

2452

3678

4904

6130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0171

AC:

2603

AN:

152168

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1155

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00499

AC:

207

AN:

41496

American (AMR)

AF:

0.0126

AC:

192

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0383

AC:

133

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00269

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00886

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0283

AC:

1923

AN:

67980

Other (OTH)

AF:

0.0175

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

133

265

398

530

663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0267

Hom.:

189

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

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

ADCY6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

Eigen

Benign

0.18

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

4.7

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.4

REVEL

Benign

0.11

Sift

Benign

0.16

Sift4G

Benign

0.34

Polyphen

0.72

Vest4

0.51

MPC

0.61

ClinPred

0.020

GERP RS

3.7

Varity_R

0.24

gMVP

0.42

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over