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
Consequence
NM_005751.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Ventricular fibrillation Uncertain:1
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not provided Uncertain:1
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not specified Benign:1
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
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Cardiovascular phenotype Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at