rs35669569

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005751.5(AKAP9):c.139C>T(p.His47Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,038 control chromosomes in the GnomAD database, including 120 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. H47H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0075 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 112 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.932

Publications

21 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006234467).

BP6

Variant 7-91973801-C-T is Benign according to our data. Variant chr7-91973801-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 8 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	NM_005751.5	MANE Select	c.139C>T	p.His47Tyr	missense	Exon 2 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.139C>T	p.His47Tyr	missense	Exon 2 of 50	NP_671714.1	Q99996-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.139C>T	p.His47Tyr	missense	Exon 2 of 50	ENSP00000348573.3	Q99996-2
AKAP9	ENST00000394564.5	TSL:1	n.313C>T		non_coding_transcript_exon	Exon 2 of 7
AKAP9	ENST00000359028.7	TSL:5	c.139C>T	p.His47Tyr	missense	Exon 2 of 51	ENSP00000351922.4	A0A0A0MRF6

Frequencies

GnomAD3 genomes

AF:

0.00748

AC:

1138

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00804

AC:

2021

AN:

251216

AF XY:

0.00770

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.00335

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0142

Gnomad NFE exome

AF:

0.0132

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.0112

AC:

16320

AN:

1461816

Hom.:

112

Cov.:

AF XY:

0.0107

AC XY:

7778

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00170

AC:

AN:

33480

American (AMR)

AF:

0.00380

AC:

170

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.000452

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0140

AC:

750

AN:

53418

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0132

AC:

14705

AN:

1111962

Other (OTH)

AF:

0.00926

AC:

559

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

890

1780

2669

3559

4449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

562

1124

1686

2248

2810

<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:

0.00748

AC:

1138

AN:

152222

Hom.:

Cov.:

AF XY:

0.00736

AC XY:

548

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00229

AC:

AN:

41536

American (AMR)

AF:

0.00562

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000416

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0171

AC:

181

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0112

AC:

761

AN:

68032

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

124

187

249

311

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:

0.0100

Hom.:

Bravo

AF:

0.00702

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.00813

AC:

987

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0132

EpiControl

AF:

0.0118

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome 11 (3)

not provided (3)

not specified (3)

Atrial fibrillation;C0007194:Hypertrophic cardiomyopathy;C0018801:Heart failure;C0878544:Cardiomyopathy (1)

Cardiovascular phenotype (1)

Congenital long QT syndrome (1)

Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.32

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0062

MetaSVM

Benign

-1.0

PhyloP100

0.93

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.4

REVEL

Benign

0.054

Sift

Benign

0.23

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.23

MVP

0.42

MPC

0.059

ClinPred

0.0053

GERP RS

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.037

gMVP

0.037

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

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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