Genetic Variant AKAP12:p.Asp50Tyr (chr6-151240710-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005100.4(AKAP12):c.148G>T(p.Asp50Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000294 in 1,120,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

AKAP12
NM_005100.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.17

Variant links:

Genes affected

AKAP12 (HGNC:370): (A-kinase anchoring protein 12) The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is expressed in endothelial cells, cultured fibroblasts, and osteosarcoma cells. It associates with protein kinases A and C and phosphatase, and serves as a scaffold protein in signal transduction. This protein and RII PKA colocalize at the cell periphery. This protein is a cell growth-related protein. Antibodies to this protein can be produced by patients with myasthenia gravis. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

AKAP12 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;

BP4

Computational evidence support a benign effect (MetaRNN=0.2930526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP12	NM_005100.4 link	c.148G>T	p.Asp50Tyr	missense_variant	Exon 2 of 5	ENST00000402676.7	NP_005091.2	Q02952-1Q86TJ9
AKAP12	XM_017011517.3 link	c.148G>T	p.Asp50Tyr	missense_variant	Exon 2 of 5		XP_016867006.1	Q02952-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP12	ENST00000402676.7 link	c.148G>T	p.Asp50Tyr	missense_variant	Exon 2 of 5	5	NM_005100.4	ENSP00000384537.2		Q02952-1
AKAP12	ENST00000253332.5 link	c.148G>T	p.Asp50Tyr	missense_variant	Exon 1 of 4	1		ENSP00000253332.1		Q02952-1

Frequencies

GnomAD3 genomes

AF:

0.0000410

AC:

AN:

146356

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000910

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000277

AC:

AN:

974480

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

460362

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000328

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000295

Gnomad4 OTH exome

AF:

0.0000280

GnomAD4 genome

AF:

0.0000410

AC:

AN:

146356

Hom.:

Cov.:

AF XY:

0.0000561

AC XY:

AN XY:

71268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000910

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.148G>T (p.D50Y) alteration is located in exon 2 (coding exon 1) of the AKAP12 gene. This alteration results from a G to T substitution at nucleotide position 148, causing the aspartic acid (D) at amino acid position 50 to be replaced by a tyrosine (Y). 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

0.31

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.089

T;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.62

T;.

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;D

Vest4

0.21

MutPred

0.32

Gain of helix (P = 0.0093);Gain of helix (P = 0.0093);

MVP

0.37

MPC

0.32

ClinPred

0.87

GERP RS

4.2

Varity_R

0.21

gMVP

0.27

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