chr7-92098173-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005751.5(AKAP9):ā€‹c.10672A>Gā€‹(p.Ile3558Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,612,382 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00062 ( 0 hom., cov: 32)
Exomes š‘“: 0.00083 ( 2 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

1
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.11
Variant links:
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]
CYP51A1 (HGNC:2649): (cytochrome P450 family 51 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein participates in the synthesis of cholesterol by catalyzing the removal of the 14alpha-methyl group from lanosterol. Homologous genes are found in all three eukaryotic phyla, fungi, plants, and animals, suggesting that this is one of the oldest cytochrome P450 genes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0076205134).
BP6
Variant 7-92098173-A-G is Benign according to our data. Variant chr7-92098173-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191527.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}. Variant chr7-92098173-A-G is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 94 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AKAP9NM_005751.5 linkc.10672A>G p.Ile3558Val missense_variant Exon 43 of 50 ENST00000356239.8 NP_005742.4 Q99996-2Q6PJH3Q5GIA7
AKAP9NM_147185.3 linkc.10648A>G p.Ile3550Val missense_variant Exon 43 of 50 NP_671714.1 Q99996-3Q6PJH3Q5GIA7
AKAP9NM_001379277.1 linkc.5317A>G p.Ile1773Val missense_variant Exon 22 of 29 NP_001366206.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AKAP9ENST00000356239.8 linkc.10672A>G p.Ile3558Val missense_variant Exon 43 of 50 1 NM_005751.5 ENSP00000348573.3 Q99996-2

Frequencies

GnomAD3 genomes
AF:
0.000617
AC:
94
AN:
152236
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00111
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000779
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000769
AC:
193
AN:
250846
Hom.:
0
AF XY:
0.000730
AC XY:
99
AN XY:
135606
show subpopulations
Gnomad AFR exome
AF:
0.000432
Gnomad AMR exome
AF:
0.000956
Gnomad ASJ exome
AF:
0.00298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000925
Gnomad NFE exome
AF:
0.000961
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.000834
AC:
1217
AN:
1460028
Hom.:
2
Cov.:
29
AF XY:
0.000855
AC XY:
621
AN XY:
726478
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000984
Gnomad4 ASJ exome
AF:
0.00237
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000169
Gnomad4 NFE exome
AF:
0.000923
Gnomad4 OTH exome
AF:
0.00111
GnomAD4 genome
AF:
0.000617
AC:
94
AN:
152354
Hom.:
0
Cov.:
32
AF XY:
0.000591
AC XY:
44
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.00111
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000779
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000775
Hom.:
0
Bravo
AF:
0.000752
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.000725
AC:
88
EpiCase
AF:
0.00120
EpiControl
AF:
0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Congenital long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 30, 2024Variant summary: AKAP9 c.10672A>G (p.Ile3558Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 250846 control chromosomes. The observed variant frequency is approximately 230-fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Long QT Syndrome phenotype (3.3e-06). To our knowledge, c.10672A>G has been not been reported in the literature in individuals affected with Long QT Syndrome and no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 191527). Based on the evidence outlined above, the variant was classified as likely benign. -
AKAP9-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 10, 2019This 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). -
Arrhythmogenic right ventricular cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoApr 09, 2019- -
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 23, 2025- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 13, 2018This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
19
DANN
Benign
0.95
DEOGEN2
Benign
0.18
T;T;.
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.21
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.73
T;T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.0076
T;T;T
MetaSVM
Benign
-0.89
T
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.27
N;N;N
REVEL
Benign
0.045
Sift
Benign
0.042
D;T;T
Sift4G
Benign
0.20
.;.;T
Vest4
0.17
MVP
0.19
MPC
0.048
ClinPred
0.038
T
GERP RS
0.64
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.025
gMVP
0.048

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144054367; hg19: chr7-91727487; COSMIC: COSV62352026; COSMIC: COSV62352026; API