NM_005751.5:c.4519G>C

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.4519G>C(p.Asp1507His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,613,820 control chromosomes in the GnomAD database, including 4 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. D1507N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.49

Publications

6 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=0.003939867).

BP6

Variant 7-92038599-G-C is Benign according to our data. Variant chr7-92038599-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 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.4519G>C	p.Asp1507His	missense	Exon 17 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.4519G>C	p.Asp1507His	missense	Exon 17 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.4519G>C	p.Asp1507His	missense	Exon 17 of 50	ENSP00000348573.3	Q99996-2
AKAP9	ENST00000359028.7	TSL:5	c.4519G>C	p.Asp1507His	missense	Exon 17 of 51	ENSP00000351922.4	A0A0A0MRF6
AKAP9	ENST00000681412.1		c.4519G>C	p.Asp1507His	missense	Exon 17 of 49	ENSP00000506486.1	A0A7P0TBH8

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

365

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00825

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000770

AC:

193

AN:

250698

AF XY:

0.000634

show subpopulations

Gnomad AFR exome

AF:

0.00997

Gnomad AMR exome

AF:

0.000811

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.000231

AC:

338

AN:

1461534

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

156

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.00834

AC:

279

AN:

33466

American (AMR)

AF:

0.000850

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111870

Other (OTH)

AF:

0.000331

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.00240

AC:

366

AN:

152286

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00825

AC:

343

AN:

41564

American (AMR)

AF:

0.00118

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68016

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

103

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:

0.000781

Hom.:

Bravo

AF:

0.00284

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000923

AC:

112

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

AKAP9-related disorder (1)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Long QT syndrome (1)

Long QT syndrome 11 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.32

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.98

PhyloP100

2.5

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.40

REVEL

Benign

0.056

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0090

Vest4

0.27

MVP

0.37

MPC

0.33

ClinPred

0.028

GERP RS

4.4

Varity_R

0.11

gMVP

0.35

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over