rs1554453992

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005751.5(AKAP9):​c.8200A>C​(p.Ser2734Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 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)

Consequence

AKAP9
NM_005751.5 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.766
Variant links:
Genes affected
AKAP9 (HGNC:379): (A-kinase anchoring protein 9) 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. Alternate splicing of this gene results in at least two isoforms that localize to the centrosome and the Golgi apparatus, and interact with numerous signaling proteins from multiple signal transduction pathways. These signaling proteins include type II protein kinase A, serine/threonine kinase protein kinase N, protein phosphatase 1, protein phosphatase 2a, protein kinase C-epsilon and phosphodiesterase 4D3. [provided by RefSeq, Aug 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06457198).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AKAP9NM_005751.5 linkuse as main transcriptc.8200A>C p.Ser2734Arg missense_variant 33/50 ENST00000356239.8 NP_005742.4
AKAP9NM_147185.3 linkuse as main transcriptc.8176A>C p.Ser2726Arg missense_variant 33/50 NP_671714.1
AKAP9NM_001379277.1 linkuse as main transcriptc.2845A>C p.Ser949Arg missense_variant 12/29 NP_001366206.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AKAP9ENST00000356239.8 linkuse as main transcriptc.8200A>C p.Ser2734Arg missense_variant 33/501 NM_005751.5 ENSP00000348573 P4Q99996-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 05, 2017This sequence change replaces serine with arginine at codon 2734 of the AKAP9 protein (p.Ser2734Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with AKAP9-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
18
DANN
Benign
0.92
DEOGEN2
Benign
0.32
.;T;T;.
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.36
N
LIST_S2
Benign
0.63
T;T;T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.065
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.7
N;.;.;N
REVEL
Benign
0.074
Sift
Benign
0.22
T;.;.;T
Sift4G
Benign
0.53
.;T;.;T
Vest4
0.15
MVP
0.30
MPC
0.14
ClinPred
0.11
T
GERP RS
-0.41
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.043
gMVP
0.16

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.

Other links and lift over

dbSNP: rs1554453992; hg19: chr7-91712523; API