NM_005751.5:c.8375A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005751.5(AKAP9):c.8375A>G(p.Asn2792Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,613,262 control chromosomes in the GnomAD database, including 116,125 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2792H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.34 ( 9247 hom., cov: 32)

Exomes 𝑓: 0.38 ( 106878 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.334

Publications

63 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=5.6543946E-4).

BP6

Variant 7-92083384-A-G is Benign according to our data. Variant chr7-92083384-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP9	NM_005751.5 link	c.8375A>G	p.Asn2792Ser	missense_variant	Exon 33 of 50	ENST00000356239.8	NP_005742.4	Q99996-2Q6PJH3Q5GIA7
AKAP9	NM_147185.3 link	c.8351A>G	p.Asn2784Ser	missense_variant	Exon 33 of 50		NP_671714.1	Q99996-3Q6PJH3Q5GIA7
AKAP9	NM_001379277.1 link	c.3020A>G	p.Asn1007Ser	missense_variant	Exon 12 of 29		NP_001366206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 link	c.8375A>G	p.Asn2792Ser	missense_variant	Exon 33 of 50	1	NM_005751.5	ENSP00000348573.3		Q99996-2

Frequencies

GnomAD3 genomes

AF:

0.340

AC:

51609

AN:

151960

Hom.:

9249

Cov.:

show subpopulations

Gnomad AFR

AF:

0.252

Gnomad AMI

AF:

0.233

Gnomad AMR

AF:

0.338

Gnomad ASJ

AF:

0.543

Gnomad EAS

AF:

0.172

Gnomad SAS

AF:

0.385

Gnomad FIN

AF:

0.386

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.369

GnomAD2 exomes

AF:

0.359

AC:

89641

AN:

249908

AF XY:

0.366

show subpopulations

Gnomad AFR exome

AF:

0.249

Gnomad AMR exome

AF:

0.298

Gnomad ASJ exome

AF:

0.546

Gnomad EAS exome

AF:

0.171

Gnomad FIN exome

AF:

0.392

Gnomad NFE exome

AF:

0.390

Gnomad OTH exome

AF:

0.383

GnomAD4 exome

AF:

0.379

AC:

553710

AN:

1461184

Hom.:

106878

Cov.:

AF XY:

0.380

AC XY:

276338

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.248

AC:

8294

AN:

33464

American (AMR)

AF:

0.301

AC:

13476

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.541

AC:

14132

AN:

26132

East Asian (EAS)

AF:

0.185

AC:

7330

AN:

39672

South Asian (SAS)

AF:

0.389

AC:

33550

AN:

86250

European-Finnish (FIN)

AF:

0.387

AC:

20608

AN:

53286

Middle Eastern (MID)

AF:

0.418

AC:

2412

AN:

5768

European-Non Finnish (NFE)

AF:

0.388

AC:

431254

AN:

1111520

Other (OTH)

AF:

0.375

AC:

22654

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

18668

37337

56005

74674

93342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13428

26856

40284

53712

67140

<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:

0.339

AC:

51620

AN:

152078

Hom.:

9247

Cov.:

AF XY:

0.339

AC XY:

25231

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.251

AC:

10423

AN:

41478

American (AMR)

AF:

0.338

AC:

5161

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.543

AC:

1884

AN:

3472

East Asian (EAS)

AF:

0.173

AC:

892

AN:

5166

South Asian (SAS)

AF:

0.385

AC:

1858

AN:

4820

European-Finnish (FIN)

AF:

0.386

AC:

4077

AN:

10566

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.386

AC:

26222

AN:

67980

Other (OTH)

AF:

0.368

AC:

776

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1717

3434

5151

6868

8585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.373

Hom.:

28077

Bravo

AF:

0.331

TwinsUK

AF:

0.377

AC:

1397

ALSPAC

AF:

0.392

AC:

1511

ESP6500AA

AF:

0.268

AC:

1180

ESP6500EA

AF:

0.401

AC:

3451

ExAC

AF:

0.359

AC:

43538

Asia WGS

AF:

0.294

AC:

1026

AN:

3478

EpiCase

AF:

0.392

EpiControl

AF:

0.402

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Aug 11, 2020

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 08, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Long QT syndrome 11

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 18, 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

0.071

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.0

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.27

.;T;T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.77

T;T;T;T

MetaRNN

Benign

0.00057

T;T;T;T

MetaSVM

Benign

-0.92

PhyloP100

0.33

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.0

N;.;.;N

REVEL

Benign

0.070

Sift

Benign

0.23

T;.;.;T

Sift4G

Benign

0.87

.;T;.;T

Vest4

0.061

MPC

0.046

ClinPred

0.0056

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.016

gMVP

0.078

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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