rs139612565

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_005751.5(AKAP9):c.4190A>G(p.Gln1397Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,613,248 control chromosomes in the GnomAD database, including 1 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. Q1397E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.433

Publications

7 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009416819).

BP6

Variant 7-92029936-A-G is Benign according to our data. Variant chr7-92029936-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191516.

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.4190A>G	p.Gln1397Arg	missense	Exon 15 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.4190A>G	p.Gln1397Arg	missense	Exon 15 of 50	NP_671714.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.4190A>G	p.Gln1397Arg	missense	Exon 15 of 50	ENSP00000348573.3
AKAP9	ENST00000359028.7	TSL:5	c.4190A>G	p.Gln1397Arg	missense	Exon 15 of 51	ENSP00000351922.4
AKAP9	ENST00000681412.1		c.4190A>G	p.Gln1397Arg	missense	Exon 15 of 49	ENSP00000506486.1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000406

AC:

102

AN:

251388

AF XY:

0.000501

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000287

AC:

420

AN:

1461036

Hom.:

Cov.:

AF XY:

0.000340

AC XY:

247

AN XY:

726900

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33436

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00276

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39604

South Asian (SAS)

AF:

0.00161

AC:

139

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00765

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000121

AC:

135

AN:

1111410

Other (OTH)

AF:

0.000431

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000151

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000329

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000437

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome (2)

not provided (2)

AKAP9-related disorder (1)

Cardiovascular phenotype (1)

Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.57

CADD

Benign

7.5

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.25

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.73

M_CAP

Benign

0.0024

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.90

PhyloP100

-0.43

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.49

REVEL

Benign

0.027

Sift

Benign

0.37

Sift4G

Benign

0.82

Vest4

0.20

MVP

0.099

MPC

0.057

ClinPred

0.018

GERP RS

1.8

Varity_R

0.028

gMVP

0.075

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over