7-92003143-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005751.5(AKAP9):​c.3226C>G​(p.Pro1076Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,784 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1076S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.17665917).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AKAP9NM_005751.5 linkc.3226C>G p.Pro1076Ala missense_variant Exon 8 of 50 ENST00000356239.8 NP_005742.4 Q99996-2Q6PJH3Q5GIA7
AKAP9NM_147185.3 linkc.3226C>G p.Pro1076Ala missense_variant Exon 8 of 50 NP_671714.1 Q99996-3Q6PJH3Q5GIA7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AKAP9ENST00000356239.8 linkc.3226C>G p.Pro1076Ala missense_variant Exon 8 of 50 1 NM_005751.5 ENSP00000348573.3 Q99996-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000404
AC:
1
AN:
247684
AF XY:
0.00000746
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000896
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458784
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
725642
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33288
American (AMR)
AF:
0.00
AC:
0
AN:
44442
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25974
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39624
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85648
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53264
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5746
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1110568
Other (OTH)
AF:
0.00
AC:
0
AN:
60230
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Long QT syndrome Uncertain:1
Sep 19, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces proline with alanine at codon 1076 of the AKAP9 protein (p.Pro1076Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs774196711, ExAC 0.002%). This variant has not been reported in the literature in individuals with AKAP9-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
15
DANN
Benign
0.95
DEOGEN2
Benign
0.33
.;.;T;T
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.086
N
LIST_S2
Uncertain
0.91
D;D;D;D
M_CAP
Benign
0.0048
T
MetaRNN
Benign
0.18
T;T;T;T
MetaSVM
Benign
-0.98
T
PhyloP100
1.8
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.9
N;.;.;.
REVEL
Benign
0.027
Sift
Uncertain
0.019
D;.;.;.
Sift4G
Benign
0.22
.;T;T;.
Vest4
0.20
MVP
0.30
MPC
0.34
ClinPred
0.14
T
GERP RS
3.1
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8
Varity_R
0.048
gMVP
0.050
Mutation Taster
=89/11
polymorphism

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

Other links and lift over

dbSNP: rs774196711; hg19: chr7-91632457; API