15-85655513-G-A

Variant summary

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

The NM_007200.5(AKAP13):​c.4471G>A​(p.Val1491Met) 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 1,461,888 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

AKAP13
NM_007200.5 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63
Variant links:
Genes affected
AKAP13 (HGNC:371): (A-kinase anchoring protein 13) 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. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms containing c-terminal dbl oncogene homology (DH) and pleckstrin homology (PH) domains. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway, function as protein kinase A-anchoring proteins and, in addition, enhance ligand-dependent activity of estrogen receptors alpha and beta. [provided by RefSeq, Jul 2012]
AKAP13-AS1 (HGNC:55975): (AKAP13 antisense RNA 1)

Genome browser will be placed here

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=0.18171206).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AKAP13NM_007200.5 linkc.4471G>A p.Val1491Met missense_variant Exon 11 of 37 ENST00000394518.7 NP_009131.2 Q12802-1
AKAP13NM_006738.6 linkc.4471G>A p.Val1491Met missense_variant Exon 11 of 37 NP_006729.4 Q12802-2
AKAP13NM_001270546.1 linkc.391G>A p.Val131Met missense_variant Exon 4 of 29 NP_001257475.1 Q12802A8MYJ1B0AZU4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AKAP13ENST00000394518.7 linkc.4471G>A p.Val1491Met missense_variant Exon 11 of 37 1 NM_007200.5 ENSP00000378026.3 Q12802-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251442
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727242
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 22, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4471G>A (p.V1491M) alteration is located in exon 11 (coding exon 10) of the AKAP13 gene. This alteration results from a G to A substitution at nucleotide position 4471, causing the valine (V) at amino acid position 1491 to be replaced by a methionine (M). 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
0.12
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.041
T;T;.;.;T;.;T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Benign
0.76
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D;D
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.18
T;T;T;T;T;T;T
MetaSVM
Benign
-0.73
T
MutationAssessor
Benign
1.2
.;L;L;.;.;.;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.6
N;N;N;.;.;.;N
REVEL
Benign
0.11
Sift
Uncertain
0.0020
D;D;D;.;.;.;D
Sift4G
Benign
0.091
T;D;D;D;D;D;D
Polyphen
0.86, 0.91
.;P;P;.;.;.;.
Vest4
0.47, 0.48, 0.40, 0.42
MutPred
0.13
Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);.;.;.;.;
MVP
0.53
MPC
0.16
ClinPred
0.68
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.091
gMVP
0.094

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs772871547; hg19: chr15-86198744; API