rs539375675

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005751.5(AKAP9):​c.509A>T​(p.Glu170Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E170D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

6
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.38
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06865546).
BP6
Variant 7-91992988-A-T is Benign according to our data. Variant chr7-91992988-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 571586.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AKAP9NM_005751.5 linkuse as main transcriptc.509A>T p.Glu170Val missense_variant 5/50 ENST00000356239.8 NP_005742.4 Q99996-2Q6PJH3Q5GIA7
AKAP9NM_147185.3 linkuse as main transcriptc.509A>T p.Glu170Val missense_variant 5/50 NP_671714.1 Q99996-3Q6PJH3Q5GIA7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AKAP9ENST00000356239.8 linkuse as main transcriptc.509A>T p.Glu170Val missense_variant 5/501 NM_005751.5 ENSP00000348573.3 Q99996-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152174
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251338
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135844
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000381
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461828
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000176
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152292
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Long QT syndrome 11 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021AKAP9 NM_005751.4 exon 5 p.Glu170Val (c.509A>T): This variant has not been reported in the literature but is present in 0.03% (7/18392) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-91622302-A-T). This variant is present in ClinVar (Variation ID:571586). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 14, 2023This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 170 of the AKAP9 protein (p.Glu170Val). This variant is present in population databases (rs539375675, gnomAD 0.03%). 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: 571586). 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 disruptive. 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 Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 07, 2023This 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
Uncertain
0.37
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.32
T;.;T;T;T;.
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.86
D;D;T;D;D;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.069
T;T;T;T;T;T
MetaSVM
Benign
-0.82
T
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-2.8
D;.;D;D;.;D
REVEL
Benign
0.099
Sift
Benign
0.081
T;.;T;D;.;T
Sift4G
Benign
0.17
.;T;D;T;.;D
Polyphen
0.64
.;.;P;.;.;.
Vest4
0.56
MutPred
0.18
Gain of methylation at K167 (P = 0.0458);.;Gain of methylation at K167 (P = 0.0458);Gain of methylation at K167 (P = 0.0458);.;.;
MVP
0.53
MPC
0.37
ClinPred
0.37
T
GERP RS
5.4
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.7
Varity_R
0.15
gMVP
0.29

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs539375675; hg19: chr7-91622302; API