rs139965373
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_005751.5(AKAP9):c.3580G>A(p.Ala1194Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000385 in 1,613,196 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1194G) has been classified as Uncertain significance.
Frequency
Consequence
NM_005751.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AKAP9 | NM_005751.5 | c.3580G>A | p.Ala1194Thr | missense_variant | 10/50 | ENST00000356239.8 | |
AKAP9 | NM_147185.3 | c.3580G>A | p.Ala1194Thr | missense_variant | 10/50 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AKAP9 | ENST00000356239.8 | c.3580G>A | p.Ala1194Thr | missense_variant | 10/50 | 1 | NM_005751.5 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000368 AC: 56AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000605 AC: 152AN: 251174Hom.: 1 AF XY: 0.000648 AC XY: 88AN XY: 135746
GnomAD4 exome AF: 0.000387 AC: 565AN: 1460940Hom.: 2 Cov.: 29 AF XY: 0.000421 AC XY: 306AN XY: 726804
GnomAD4 genome AF: 0.000368 AC: 56AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74450
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | AKAP9: BP4, BS1, BS2 - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | May 17, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 25, 2018 | The AKAP9 c.3580G>A; p.Ala1194Thr variant (rs139965373, ClinVar variant ID 180262) has been detected in large whole-exome datasets from a cohort of SIDS patients (Neubauer 2017) and an unselected population (Ng 2013). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.06% (identified on 159 out of 276,956 chromosomes, including one homozygote). The alanine at position 1194 is highly conserved, considering 11 species, and computational analyses of the effects of the p.Ala1194Thr variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Ala1194Thr variant cannot be determined with certainty. - |
Long QT syndrome 11 Uncertain:1
Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Sep 30, 2015 | - - |
Congenital long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 18, 2019 | Variant summary: AKAP9 c.3580G>A (p.Ala1194Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251174 control chromosomes, predominantly at a frequency of 0.00095 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 95 fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3580G>A has been reported in the literature in individuals affected with Sudden infant death syndrome, Hypertrophic Cardiomyopathy and prostate cancer (Neubauer_2017, Forleo_2017, Belic_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Additionally, co-occurrences with other pathogenic variants have been reported (MYBPC3 c.506-2A>C; BRCA2 c.4091_4092insAA, p.I1364fs) (Forleo_2017, Belic_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and uncertain significance (5x). Based on the evidence outlined above, the variant was classified as likely benign. - |
AKAP9-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 05, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Ventricular fibrillation Benign:1
Likely benign, no assertion criteria provided | clinical testing | Blueprint Genetics | May 26, 2014 | - - |
Long QT syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 25, 2019 | This alteration is classified as likely 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at