NM_005751.5:c.8656A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_005751.5(AKAP9):​c.8656A>G​(p.Ile2886Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,608,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. I2886L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -3.71

Publications

5 publications found
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]
AKAP9 Gene-Disease associations (from GenCC):
  • male infertility with azoospermia or oligozoospermia due to single gene mutation
    Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
  • long QT syndrome 11
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • long QT syndrome
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.01799485).
BP6
Variant 7-92084649-A-G is Benign according to our data. Variant chr7-92084649-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 222489.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AKAP9NM_005751.5 linkc.8656A>G p.Ile2886Val missense_variant Exon 34 of 50 ENST00000356239.8 NP_005742.4 Q99996-2Q6PJH3Q5GIA7
AKAP9NM_147185.3 linkc.8632A>G p.Ile2878Val missense_variant Exon 34 of 50 NP_671714.1 Q99996-3Q6PJH3Q5GIA7
AKAP9NM_001379277.1 linkc.3301A>G p.Ile1101Val missense_variant Exon 13 of 29 NP_001366206.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AKAP9ENST00000356239.8 linkc.8656A>G p.Ile2886Val missense_variant Exon 34 of 50 1 NM_005751.5 ENSP00000348573.3 Q99996-2

Frequencies

GnomAD3 genomes
AF:
0.000250
AC:
38
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000412
Gnomad OTH
AF:
0.000956
GnomAD2 exomes
AF:
0.000188
AC:
47
AN:
250340
AF XY:
0.000185
show subpopulations
Gnomad AFR exome
AF:
0.000125
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000344
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000373
AC:
543
AN:
1456674
Hom.:
0
Cov.:
28
AF XY:
0.000338
AC XY:
245
AN XY:
724842
show subpopulations
African (AFR)
AF:
0.000120
AC:
4
AN:
33320
American (AMR)
AF:
0.000157
AC:
7
AN:
44684
Ashkenazi Jewish (ASJ)
AF:
0.0000384
AC:
1
AN:
26072
East Asian (EAS)
AF:
0.0000758
AC:
3
AN:
39584
South Asian (SAS)
AF:
0.0000350
AC:
3
AN:
85820
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53382
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5632
European-Non Finnish (NFE)
AF:
0.000462
AC:
512
AN:
1107986
Other (OTH)
AF:
0.000199
AC:
12
AN:
60194
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
22
45
67
90
112
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000250
AC:
38
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.000282
AC XY:
21
AN XY:
74348
show subpopulations
African (AFR)
AF:
0.0000965
AC:
4
AN:
41442
American (AMR)
AF:
0.000196
AC:
3
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000192
AC:
1
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000412
AC:
28
AN:
68036
Other (OTH)
AF:
0.000956
AC:
2
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.516
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000310
Hom.:
1
Bravo
AF:
0.000261
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000350
AC:
3
ExAC
AF:
0.000181
AC:
22
EpiCase
AF:
0.0000546
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:2
Sep 18, 2015
Blueprint Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 21, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: AKAP9 c.8656A>G (p.Ile2886Val) 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 0.00019 in 282002 control chromosomes (gnomAD, Le Scouarnec_2015), predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 99 fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Long QT Syndrome (3.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.8656A>G has been reported in the literature in individuals affected with Brugada Syndrome as well as in asymptomatic individuals (Allegue_2015, Campuzano_2019). These reports do 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 publications have been ascertained in the context of this evaluation (PMID: 26230511, 30821013, 25650408). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Long QT syndrome Uncertain:1
Dec 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2886 of the AKAP9 protein (p.Ile2886Val). This variant is present in population databases (rs143283097, gnomAD 0.03%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26230511). ClinVar contains an entry for this variant (Variation ID: 222489). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
Apr 24, 2019
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.058
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
0.0010
DANN
Benign
0.19
DEOGEN2
Benign
0.22
.;T;.
Eigen
Benign
-2.2
Eigen_PC
Benign
-2.3
FATHMM_MKL
Benign
0.0051
N
LIST_S2
Benign
0.45
T;T;T
M_CAP
Benign
0.0040
T
MetaRNN
Benign
0.018
T;T;T
MetaSVM
Benign
-1.1
T
PhyloP100
-3.7
PrimateAI
Benign
0.23
T
PROVEAN
Benign
0.13
N;.;N
REVEL
Benign
0.031
Sift
Benign
0.54
T;.;T
Sift4G
Benign
0.98
.;T;T
Vest4
0.029
MVP
0.12
MPC
0.047
ClinPred
0.012
T
GERP RS
-10
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.015
gMVP
0.058
Mutation Taster
=89/11
polymorphism

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

Other links and lift over

dbSNP: rs143283097; hg19: chr7-91713963; API