chr7-92052885-T-C
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_005751.5(AKAP9):c.5528T>C(p.Met1843Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1843K) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
AKAP9
NM_005751.5 missense
NM_005751.5 missense
Scores
6
10
Clinical Significance
Conservation
PhyloP100: 4.16
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 -4 ACMG points.
BS2
High AC in GnomAdExome4 at 18 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AKAP9 | NM_005751.5 | c.5528T>C | p.Met1843Thr | missense_variant | 22/50 | ENST00000356239.8 | |
AKAP9 | NM_147185.3 | c.5528T>C | p.Met1843Thr | missense_variant | 22/50 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AKAP9 | ENST00000356239.8 | c.5528T>C | p.Met1843Thr | missense_variant | 22/50 | 1 | NM_005751.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251058Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135676
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461590Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727086
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GnomAD4 genome Cov.: 32
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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 | Invitae | Jan 05, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1843 of the AKAP9 protein (p.Met1843Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with AKAP9-related conditions. ClinVar contains an entry for this variant (Variation ID: 457112). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2022 | The c.5528T>C (p.M1843T) alteration is located in exon 22 (coding exon 22) of the AKAP9 gene. This alteration results from a T to C substitution at nucleotide position 5528, causing the methionine (M) at amino acid position 1843 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Uncertain
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;.
REVEL
Benign
Sift
Uncertain
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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