7-91992989-G-C

Variant names:

• chr7-91992989-G-C
• rs144888041
• NM_005751.5:c.510G>C

Variant summary

Our verdict is Benign. The variant received -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. 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. 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
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 190518.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005751.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	NM_005751.5	MANE Select	c.510G>C	p.Glu170Asp	missense	Exon 5 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.510G>C	p.Glu170Asp	missense	Exon 5 of 50	NP_671714.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.510G>C	p.Glu170Asp	missense	Exon 5 of 50	ENSP00000348573.3
	AKAP9	ENST00000394564.5	TSL:1	n.684G>C		non_coding_transcript_exon	Exon 5 of 7
	AKAP9	ENST00000359028.7	TSL:5	c.510G>C	p.Glu170Asp	missense	Exon 5 of 51	ENSP00000351922.4

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

GnomAD2 exomes AF: 0.00191 AC: 481 AN: 251328 AF XY: 0.00174

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 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

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00420 AC: 188 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00328 AC: 3643 AN: 1111964

Other (OTH) AF: 0.00270 AC: 163 AN: 60388

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152276 Hom.: 1 Cov.: 31 AF XY: 0.00197 AC XY: 147 AN XY: 74458

African (AFR) AF: 0.000505 AC: 21 AN: 41554

American (AMR) AF: 0.00445 AC: 68 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AKAP9: BS1, BS2

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

Feb 23, 2012

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Sep 29, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:3

Aug 16, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Congenital long QT syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Brugada syndrome 1 Benign:1

Mar 16, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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

Dec 18, 2017

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome 11 Benign:1

Dec 13, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Nov 09, 2018

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 v4.9

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
Eigen	Benign	-0.12
Eigen_PC	Benign	0.0095
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.15
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.043
Sift	Benign	0.15	T
Sift4G	Benign	0.23	T
Polyphen		0.058	B
Vest4		0.40
MutPred		0.10		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
Mutation Taster		=99/1	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

Other links and lift over

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