rs144888041

Positions:

chr7-91992989-G-C

Variant summary

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

The ENST00000356239.8(AKAP9):c.510G>C(p.Glu170Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,614,098 control chromosomes in the GnomAD database, including 12 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E170V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0028 ( 11 hom. )

Consequence

AKAP9
ENST00000356239.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 0.150

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047680736).

BP6

Variant 7-91992989-G-C is Benign according to our data. Variant chr7-91992989-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190518.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=2, Likely_benign=4}. Variant chr7-91992989-G-C is described in Lovd as [Benign]. Variant chr7-91992989-G-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 317 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP9	NM_005751.5 linkuse as main transcript	c.510G>C	p.Glu170Asp	missense_variant	5/50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3 linkuse as main transcript	c.510G>C	p.Glu170Asp	missense_variant	5/50		NP_671714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 linkuse as main transcript	c.510G>C	p.Glu170Asp	missense_variant	5/50	1	NM_005751.5	ENSP00000348573	P4	Q99996-2

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

317

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00303

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00191

AC:

481

AN:

251328

Hom.:

AF XY:

0.00174

AC XY:

236

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00393

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00264

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00277

AC:

4054

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

1925

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00420

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000468

Gnomad4 NFE exome

AF:

0.00328

Gnomad4 OTH exome

AF:

0.00270

GnomAD4 genome

AF:

0.00208

AC:

317

AN:

152276

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00445

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00303

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00232

Hom.:

Bravo

AF:

0.00234

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00180

AC:

218

EpiCase

AF:

0.00224

EpiControl

AF:

0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2012	p.E170D:GAG>GAC at the protein level, c.510 G>C at the DNA level. A heterozygous G>C nucleotide substitution was identified in exon 6 of the AKAP9 gene, resulting in replacement of the normal Glutamic acid codon (GAG) with an Aspartic acid codon (GAC) at amino acid position 170 in the A-kinase anchor protein 9. This missense change is denoted Glu170Asp (aka E170D) at the protein level and c.510 G>C at the cDNA level. The Glu170Asp variant in the AKAP9 gene has not been previously reported as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The Glu170Asp variant was not detected in 600 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign variant in these populations. However, Glu170Asp results in a conservative substitution of a negatively charged amino acid with another at a position that is not highly conserved across species. In addition, no missense mutations have been reported in nearby codons of the AKAP9 gene, and Glu170Asp does not occur in or near either of the two known binding sites of AKAP9, indicating this region of the protein may be tolerant of change. With the molecular and clinical information available, we cannot determine the clinical significance of Glu170Asp and classify it as a variant of unknown clinical significance at this time. The variant is found in LQT panel(s). -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	AKAP9: BS1, BS2 -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2021	Variant summary: AKAP9 c.510G>C (p.Glu170Asp) 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 0.0019 in 251328 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 574 fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Long QT Syndrome phenotype (3.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.510G>C in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=6). Based on the evidence outlined above, the variant was classified as benign. -

Congenital long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Brugada syndrome 1

Benign:1

Benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 16, 2017

The AKAP9 Glu170Asp has been previously identified in a Marfan Syndrome case, the patient also carried a FBN1 Cys2592Arg variant (Garzon SS, 2015). The AKAP9 Glu170Asp variant is found at high frequency in the Exome Aggregation Consortium dataset (MAF= 0.002; http://exac.broadinstitute.org/), suggesting that it is a common polymorphism (Ng D, et al., 2013). We identified this variant in one proband with Brugada syndrome, who has no family history of disease or SCD. The proband also carries a rare variant (RYR2 Asp1412Gly). Furthermore, computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to be well tolerated. Based on a high allele frequency in the general population and in silico tools predicting no deleterious affect on the protein, we classify this variant as "benign". -

Catecholaminergic polymorphic ventricular tachycardia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Dec 18, 2017

- -

Long QT syndrome 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Dec 13, 2016

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2018

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

0.23

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.28

T;.;T;T;T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.0095

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.80

T;T;T;T;T;T

M_CAP

Benign

0.0062

MetaRNN

Benign

0.0048

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.93

N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.3

N;.;N;N;.;N

REVEL

Benign

0.043

Sift

Benign

0.15

T;.;T;D;.;T

Sift4G

Benign

0.23

.;T;T;T;.;D

Polyphen

0.058

.;.;B;.;.;.

Vest4

0.40

MutPred

0.10

Gain of loop (P = 0.024);.;Gain of loop (P = 0.024);Gain of loop (P = 0.024);.;.;

MVP

0.43

MPC

0.086

ClinPred

0.011

GERP RS

4.5

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.062

gMVP

0.20

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over