12-48768686-C-T

Position:

chr12-48768686-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_015270.5(ADCY6):c.3412G>A(p.Ala1138Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADCY6
NM_015270.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.56

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:

TEX49 (HGNC:):

TEX49 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.11917156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY6	NM_015270.5 linkuse as main transcript	c.3412G>A	p.Ala1138Thr	missense_variant	22/22	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.3412G>A	p.Ala1138Thr	missense_variant	22/22	2	NM_015270.5	ENSP00000350536	P1	O43306-1
ADCY6	ENST00000307885.4 linkuse as main transcript	c.3412G>A	p.Ala1138Thr	missense_variant	21/21	1		ENSP00000311405	P1	O43306-1
ADCY6	ENST00000550422.5 linkuse as main transcript	c.3253G>A	p.Ala1085Thr	missense_variant	21/21	2		ENSP00000446730		O43306-2
ADCY6	ENST00000547260.5 linkuse as main transcript	n.2266G>A		non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250626

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135534

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.3412G>A (p.A1138T) alteration is located in exon 21 (coding exon 21) of the ADCY6 gene. This alteration results from a G to A substitution at nucleotide position 3412, causing the alanine (A) at amino acid position 1138 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

.;.;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;.;D

M_CAP

Benign

0.0071

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.12

.;.;N

MutationTaster

Benign

0.72

N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.076

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.67

T;T;T

Polyphen

0.72

P;P;B

Vest4

0.28

MutPred

0.42

.;.;Gain of catalytic residue at L1136 (P = 5e-04);

MVP

0.37

MPC

0.53

ClinPred

0.42

GERP RS

4.0

Varity_R

0.15

gMVP

0.29

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

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