rs755140795
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The ENST00000356239.8(AKAP9):āc.431C>Gā(p.Ser144Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,856 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 (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 31)
Exomes š: 0.000025 ( 0 hom. )
Consequence
AKAP9
ENST00000356239.8 missense
ENST00000356239.8 missense
Scores
6
12
Clinical Significance
Conservation
PhyloP100: 1.43
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 -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.10188204).
BS2
High AC in GnomAdExome4 at 36 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AKAP9 | NM_005751.5 | c.431C>G | p.Ser144Cys | missense_variant | 5/50 | ENST00000356239.8 | NP_005742.4 | |
AKAP9 | NM_147185.3 | c.431C>G | p.Ser144Cys | missense_variant | 5/50 | NP_671714.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AKAP9 | ENST00000356239.8 | c.431C>G | p.Ser144Cys | missense_variant | 5/50 | 1 | NM_005751.5 | ENSP00000348573 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152014Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251240Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135804
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461724Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727162
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152132Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74378
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 22, 2021 | In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "deleterious", MutationTaster: "polymorphism", Align-GVGD: "Class C65"). This variant is present in population databases (rs755140795, ExAC 0.005%) but has not been reported in the literature in individuals with a AKAP9-related disease. This sequence change replaces serine with cystine at codon 144 of the AKAP9 protein (p.Ser144Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cystine. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 30, 2022 | The p.S144C variant (also known as c.431C>G), located in coding exon 5 of the AKAP9 gene, results from a C to G substitution at nucleotide position 431. The serine at codon 144 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
.;.;T;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;D;.;.;D
REVEL
Benign
Sift
Uncertain
D;.;D;.;.;D
Sift4G
Uncertain
.;D;T;D;.;T
Polyphen
1.0
.;.;D;.;.;.
Vest4
MutPred
Loss of phosphorylation at S144 (P = 0.0235);.;Loss of phosphorylation at S144 (P = 0.0235);Loss of phosphorylation at S144 (P = 0.0235);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at