rs144888041

chr7-91992989-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005751.5(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 NM_005751.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 0.150

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]

ACMG classification

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 GnomAd at 317 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.510G>C	p.Glu170Asp	missense_variant	5/50	ENST00000356239.8
AKAP9	NM_147185.3	c.510G>C	p.Glu170Asp	missense_variant	5/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.510G>C	p.Glu170Asp	missense_variant	5/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152158 Hom.: 1 Cov.: 31

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.: 1 AF XY: 0.00174 AC XY: 236 AN XY: 135840

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.: 11 Cov.: 31 AF XY: 0.00265 AC XY: 1925 AN XY: 727214

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.: 1 Cov.: 31 AF XY: 0.00197 AC XY: 147 AN XY: 74458

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.: 0

Bravo AF: 0.00234

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00180 AC: 218

EpiCase AF: 0.00224

EpiControl AF: 0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	AKAP9: BS1, BS2 -
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). -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 29, 2017	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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". -

Long QT syndrome 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Dec 13, 2016

- -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	17
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	D
LIST_S2	Benign	0.80	T;T;T;T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0048	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.93	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;.;N;N;.;N
REVEL	Benign	0.043
Sift	Benign	0.15	T;.;T;D;.;T
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	T
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

Other links and lift over

dbSNP: rs144888041; hg19: chr7-91622303; COSMIC: COSV99072576;