NM_005751.5:c.5978-4A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_005751.5(AKAP9):c.5978-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,551,668 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 11 hom. )

Consequence

AKAP9
NM_005751.5 splice_region, intron

Scores

Splicing: ADA: 0.9986

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 2.63

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 7-92065227-A-G is Benign according to our data. Variant chr7-92065227-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220501.

BS2

High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
AKAP9	NM_005751.5 link	c.5978-4A>G	splice_region_variant, intron_variant	Intron 24 of 49	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3 link	c.5978-4A>G	splice_region_variant, intron_variant	Intron 24 of 49		NP_671714.1
AKAP9	NM_001379277.1 link	c.623-4A>G	splice_region_variant, intron_variant	Intron 3 of 28		NP_001366206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 link	c.5978-4A>G		splice_region_variant, intron_variant	Intron 24 of 49	1	NM_005751.5	ENSP00000348573.3

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000849

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00318

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00190

AC:

464

AN:

244260

AF XY:

0.00181

show subpopulations

Gnomad AFR exome

AF:

0.000648

Gnomad AMR exome

AF:

0.0000586

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000747

Gnomad NFE exome

AF:

0.00385

Gnomad OTH exome

AF:

0.00218

GnomAD4 exome

AF:

0.00343

AC:

4805

AN:

1399384

Hom.:

Cov.:

AF XY:

0.00324

AC XY:

2267

AN XY:

699860

show subpopulations

African (AFR)

AF:

0.000534

AC:

AN:

31850

American (AMR)

AF:

0.0000678

AC:

AN:

44280

Ashkenazi Jewish (ASJ)

AF:

0.0000389

AC:

AN:

25690

East Asian (EAS)

AF:

0.00

AC:

AN:

38930

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83800

European-Finnish (FIN)

AF:

0.000998

AC:

AN:

53090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5096

European-Non Finnish (NFE)

AF:

0.00436

AC:

4612

AN:

1058582

Other (OTH)

AF:

0.00203

AC:

118

AN:

58066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

216

432

649

865

1081

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.00168

AC:

256

AN:

152284

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000673

AC:

AN:

41574

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000849

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00318

AC:

216

AN:

68022

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00264

Hom.:

Bravo

AF:

0.00168

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 27, 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.5978-4A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0019 in 244260 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 570 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.5978-4A>G in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Long QT syndrome 11

Benign:2

Sep 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AKAP9: BS1, BS2 -

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

- -

AKAP9-related disorder

Benign:1

May 08, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Dec 11, 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Benign

0.59

PhyloP100

2.6

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.84

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.84

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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