chr7-92040806-AG-CA
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_005751.5(AKAP9):c.4825_4826delAGinsCA(p.Arg1609Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1609R) has been classified as Benign.
Frequency
Genomes: not found (cov: 31)
Consequence
AKAP9
NM_005751.5 missense
NM_005751.5 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.85
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 7-92040806-AG-CA is Benign according to our data. Variant chr7-92040806-AG-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190484.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=2}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Ventricular fibrillation Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 31, 2015 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Dec 31, 2019 | - - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2024 | Variant summary: AKAP9 c.4825_4826delinsCA (p.Arg1609Gln) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The allele frequency of this variant could not be determined from population databases such as gnomAD as it is a multinucleotide variant consisting of 7-91670120-A-C (c.4825A>C; p.Arg1609Arg) and 7-91670121-G-A (c.4826G>A; p.Arg1609Lys). The individual variants have variable frequencies and the exact number of alleles representing a combination of the two in cis is unknown. However, based on the frequency of the least prevalent allele, namely c.4826G>A, it can be estimated that the multinucleotide variant can be found at a frequency of 0.00027 in 1614004 control chromosomes, predominantly at a frequency of 0.0018 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 540-fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Long QT Syndrome phenotype (3.3e-06). c.4825_4826delinsCA has been reported in the literature in at least an individual affected with AKAP9-related conditions (example: Martinez-Matila_2019). This report however, does not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31376648). ClinVar contains an entry for this variant (Variation ID: 190484). Based on the evidence outlined above, the variant was classified as likely benign. - |
Long QT syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | - - |
Cardiovascular phenotype Benign:1
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2022 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at