rs146797353

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005751.5(AKAP9):c.3827G>A(p.Arg1276Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00766 in 1,570,710 control chromosomes in the GnomAD database, including 65 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1276R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0070 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 57 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.541

Publications

23 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

AKAP9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028244555).

BP6

Variant 7-92017092-G-A is Benign according to our data. Variant chr7-92017092-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00701 (1066/152140) while in subpopulation EAS AF = 0.0235 (122/5188). AF 95% confidence interval is 0.0201. There are 8 homozygotes in GnomAd4. There are 528 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP9	NM_005751.5 link	c.3827G>A	p.Arg1276Gln	missense_variant	Exon 12 of 50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3 link	c.3827G>A	p.Arg1276Gln	missense_variant	Exon 12 of 50		NP_671714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 link	c.3827G>A	p.Arg1276Gln	missense_variant	Exon 12 of 50	1	NM_005751.5	ENSP00000348573.3

Frequencies

GnomAD3 genomes

AF:

0.00702

AC:

1067

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00398

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00636

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.0237

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00701

Gnomad OTH

AF:

0.00958

GnomAD2 exomes

AF:

0.00930

AC:

2047

AN:

220076

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.00420

Gnomad AMR exome

AF:

0.00286

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.0219

Gnomad FIN exome

AF:

0.00118

Gnomad NFE exome

AF:

0.00835

Gnomad OTH exome

AF:

0.00663

GnomAD4 exome

AF:

0.00773

AC:

10971

AN:

1418570

Hom.:

Cov.:

AF XY:

0.00816

AC XY:

5758

AN XY:

705376

show subpopulations

African (AFR)

AF:

0.00394

AC:

128

AN:

32488

American (AMR)

AF:

0.00297

AC:

129

AN:

43442

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

513

AN:

25410

East Asian (EAS)

AF:

0.0206

AC:

804

AN:

39036

South Asian (SAS)

AF:

0.0164

AC:

1360

AN:

83116

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

52106

Middle Eastern (MID)

AF:

0.00773

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00681

AC:

7350

AN:

1078606

Other (OTH)

AF:

0.00965

AC:

566

AN:

58676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

504

1007

1511

2014

2518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.00701

AC:

1066

AN:

152140

Hom.:

Cov.:

AF XY:

0.00710

AC XY:

528

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00397

AC:

165

AN:

41552

American (AMR)

AF:

0.00635

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3466

East Asian (EAS)

AF:

0.0235

AC:

122

AN:

5188

South Asian (SAS)

AF:

0.0166

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00701

AC:

476

AN:

67924

Other (OTH)

AF:

0.00948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00893

Hom.:

Bravo

AF:

0.00706

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00886

AC:

ExAC

AF:

0.00878

AC:

1059

Asia WGS

AF:

0.0250

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 08, 2020

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.3827G>A (p.Arg1276Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0093 in 220076 control chromosomes in the gnomAD database, including 21 homozygotes. The observed variant frequency is approximately 2790 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Aug 04, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

not provided

Benign:3

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AKAP9: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30821013, 29177109, 26230511) -

Long QT syndrome 11

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital long QT syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Apr 23, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

0.085

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.22

.;.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.024

LIST_S2

Uncertain

0.87

D;D;D;D

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-0.90

PhyloP100

0.54

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.030

N;.;.;.

REVEL

Benign

0.014

Sift

Benign

0.60

T;.;.;.

Sift4G

Benign

0.94

.;T;T;.

Vest4

0.11

MVP

0.072

MPC

0.062

ClinPred

0.000025

GERP RS

-1.9

Varity_R

0.021

gMVP

0.057

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over