rs121908566

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_005751.5(AKAP9):c.4709C>T(p.Ser1570Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000209 in 1,291,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000022 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:1

Conservation

PhyloP100: 0.562

Publications

35 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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24796015).

BP6

Variant 7-92040690-C-T is Benign according to our data. Variant chr7-92040690-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5883.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP9	NM_005751.5 link	c.4709C>T	p.Ser1570Leu	missense_variant	Exon 18 of 50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3 link	c.4709C>T	p.Ser1570Leu	missense_variant	Exon 18 of 50		NP_671714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 link	c.4709C>T	p.Ser1570Leu	missense_variant	Exon 18 of 50	1	NM_005751.5	ENSP00000348573.3

Frequencies

GnomAD3 genomes

AF:

0.0000217

AC:

AN:

138374

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000138

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000305

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000820

AC:

AN:

243782

AF XY:

0.0000152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000209

AC:

AN:

1291098

Hom.:

Cov.:

AF XY:

0.0000185

AC XY:

AN XY:

647780

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28948

American (AMR)

AF:

0.00

AC:

AN:

42406

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23364

East Asian (EAS)

AF:

0.00

AC:

AN:

35684

South Asian (SAS)

AF:

0.00

AC:

AN:

81438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5214

European-Non Finnish (NFE)

AF:

0.0000278

AC:

AN:

970226

Other (OTH)

AF:

0.00

AC:

AN:

53230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000217

AC:

AN:

138374

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

66194

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

37048

American (AMR)

AF:

0.00

AC:

AN:

13228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3400

East Asian (EAS)

AF:

0.00

AC:

AN:

4554

South Asian (SAS)

AF:

0.00

AC:

AN:

4300

European-Finnish (FIN)

AF:

0.000138

AC:

AN:

7238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.0000305

AC:

AN:

65574

Other (OTH)

AF:

0.00

AC:

AN:

1868

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000625500), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000756

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000552

EpiControl

AF:

0.0000600

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 11

Pathogenic:1Uncertain:1

Dec 26, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Aug 07, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser1570Leu variant has been previously reported in association with long QT syndrome in a single family (Chen 2007). Functional studies performed by Chen et al. suggest the p.Ser1570Leu variant alters the binding between AKAP9 and KCNQ1 which results in a decrease in cyclic AMP associated current in an in vitro model system. This may prolong the action potential of cardiomyocytes but the p.Ser1570Leu variant has not been tested in cardiomyocytes. The serine at position 1570 is weakly conserved and most other non-primate mammalian species have leucine at this position suggesting this change may be evolutionally tolerated. This variant is listed in the genome Aggregation Database (gnomAD) on 2 chromosomes (identified on 2 out of 239,262 chromosomes). Altogether, there is not enough evidence to classify the p.Ser1570Leu variant with certainty. -

Long QT syndrome

Uncertain:1

Jul 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Experimental studies have shown that this missense change affects AKAP9 function (PMID: 18093912). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is present in population databases (rs121908566, gnomAD 0.002%). This missense change has been observed in individuals with long QT syndrome (PMID: 18093912). ClinVar contains an entry for this variant (Variation ID: 5883). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1570 of the AKAP9 protein (p.Ser1570Leu). -

Cardiovascular phenotype

Benign:1

Jul 13, 2022

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

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.6

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.22

.;.;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.82

T;T;T;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.94

PhyloP100

0.56

PrimateAI

Benign

0.31

PROVEAN

Benign

0.56

N;.;.;.

REVEL

Uncertain

0.29

Sift

Benign

0.49

T;.;.;.

Sift4G

Benign

0.25

.;T;T;.

Vest4

0.20

MVP

0.15

MPC

0.049

ClinPred

0.022

GERP RS

1.9

Varity_R

0.025

gMVP

0.083

Mutation Taster

=18/82

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over