Genetic Variant ADCY6:p.Ala674Thr (chr12-48775015-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015270.5(ADCY6):c.2020G>A(p.Ala674Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A674S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADCY6
NM_015270.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.70

Publications

0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypomyelination neuropathy-arthrogryposis syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ADCY6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18159091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY6	NM_015270.5 link	c.2020G>A	p.Ala674Thr	missense_variant	Exon 12 of 22	ENST00000357869.8	NP_056085.1	O43306-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADCY6	ENST00000357869.8 link	c.2020G>A	p.Ala674Thr	missense_variant	Exon 12 of 22	2	NM_015270.5	ENSP00000350536.4	O43306-1
ADCY6	ENST00000307885.4 link	c.2020G>A	p.Ala674Thr	missense_variant	Exon 11 of 21	1		ENSP00000311405.4	O43306-1
ADCY6	ENST00000550422.5 link	c.2020G>A	p.Ala674Thr	missense_variant	Exon 12 of 21	2		ENSP00000446730.1	O43306-2
ADCY6	ENST00000552090.1 link	n.542G>A		non_coding_transcript_exon_variant	Exon 6 of 8	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1406038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694136

African (AFR)

AF:

0.00

AC:

AN:

31964

American (AMR)

AF:

0.00

AC:

AN:

36256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25224

East Asian (EAS)

AF:

0.00

AC:

AN:

36408

South Asian (SAS)

AF:

0.00

AC:

AN:

79588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082644

Other (OTH)

AF:

0.00

AC:

AN:

58342

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;.;T

Eigen

Benign

-0.085

Eigen_PC

Benign

0.032

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;.;D

M_CAP

Benign

0.0064

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L;L

PhyloP100

4.7

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.061

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.065

B;B;B

Vest4

0.36

MutPred

0.37

Gain of catalytic residue at C675 (P = 2e-04);Gain of catalytic residue at C675 (P = 2e-04);Gain of catalytic residue at C675 (P = 2e-04);

MVP

0.25

MPC

0.42

ClinPred

0.82

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.48

Mutation Taster

=72/28

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over