Variant 6-151348752-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005100.4(AKAP12):c.361G>A(p.Asp121Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,415,244 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: 𝑓 0.000015 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

AKAP12
NM_005100.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.497

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0763562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP12	NM_005100.4 linkuse as main transcript	c.361G>A	p.Asp121Asn	missense_variant	4/5	ENST00000402676.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP12	ENST00000402676.7 linkuse as main transcript	c.361G>A	p.Asp121Asn	missense_variant	4/5	5	NM_005100.4	A2	Q02952-1

Frequencies

GnomAD3 genomes

AF:

0.0000152

AC:

AN:

131254

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:

0.0000308

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000101

AC:

AN:

1283990

Hom.:

Cov.:

AF XY:

0.00000785

AC XY:

AN XY:

636540

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000120

Gnomad4 OTH exome

AF:

0.0000206

GnomAD4 genome

AF:

0.0000152

AC:

AN:

131254

Hom.:

Cov.:

AF XY:

0.0000162

AC XY:

AN XY:

61680

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:

0.0000308

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The c.361G>A (p.D121N) alteration is located in exon 4 (coding exon 3) of the AKAP12 gene. This alteration results from a G to A substitution at nucleotide position 361, causing the aspartic acid (D) at amino acid position 121 to be replaced by an asparagine (N). 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

0.087

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.76

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.17

T;T;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.71

T;.;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.076

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.3

L;L;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.0

N;N;N;N

REVEL

Benign

0.058

Sift

Benign

0.081

T;T;T;T

Sift4G

Benign

0.52

T;T;T;T

Polyphen

0.65

P;P;P;P

Vest4

0.095

MutPred

0.15

Gain of methylation at K122 (P = 0.0694);Gain of methylation at K122 (P = 0.0694);.;.;

MVP

0.31

MPC

0.36

ClinPred

0.39

GERP RS

2.8

Varity_R

0.040

gMVP

0.046

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