rs750905383

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005751.5(AKAP9):c.2113T>G(p.Leu705Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,609,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L705L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.854

Publications

3 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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.075715244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP9	NM_005751.5 link	c.2113T>G	p.Leu705Val	missense_variant	Exon 8 of 50	ENST00000356239.8	NP_005742.4	Q99996-2Q6PJH3Q5GIA7
AKAP9	NM_147185.3 link	c.2113T>G	p.Leu705Val	missense_variant	Exon 8 of 50		NP_671714.1	Q99996-3Q6PJH3Q5GIA7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 link	c.2113T>G	p.Leu705Val	missense_variant	Exon 8 of 50	1	NM_005751.5	ENSP00000348573.3		Q99996-2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000123

AC:

AN:

243234

AF XY:

0.00000756

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:

0.0000272

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000686

AC:

AN:

1457038

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33228

American (AMR)

AF:

0.00

AC:

AN:

44062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39562

South Asian (SAS)

AF:

0.00

AC:

AN:

84628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1110522

Other (OTH)

AF:

0.00

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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

AF:

0.0000395

AC:

AN:

151966

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67928

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.0000544

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 11

Uncertain:1

Sep 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AKAP9-related disorder

Uncertain:1

Aug 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The AKAP9 c.2113T>G variant is predicted to result in the amino acid substitution p.Leu705Val. This variant was reported in a cohort of individuals with long QT syndrome; however, detailed clinical information was not available (supplementary material, Mullally et al. 2013. PubMed ID: 23174487). This variant is reported in 0.0032% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-91631344-T-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Long QT syndrome

Uncertain:1

Sep 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 526965). This missense change has been observed in individual(s) with long QT syndrome (PMID: 23174487). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 705 of the AKAP9 protein (p.Leu705Val). -

Cardiovascular phenotype

Uncertain:1

May 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L705V variant (also known as c.2113T>G), located in coding exon 8 of the AKAP9 gene, results from a T to G substitution at nucleotide position 2113. The leucine at codon 705 is replaced by valine, an amino acid with highly similar properties. This variant has been detected in a long QT syndrome cohort; however, clinical details were limited (Mullally J et al. Heart Rhythm, 2013 Mar;10:378-82). This amino acid position is well conserved in available vertebrate species; however, valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.35

.;.;T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.076

T;T;T;T

MetaSVM

Benign

-0.97

PhyloP100

0.85

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.6

N;.;.;.

REVEL

Benign

0.22

Sift

Uncertain

0.0030

D;.;.;.

Sift4G

Benign

0.068

.;T;T;.

Vest4

0.22

MVP

0.38

MPC

0.059

ClinPred

0.14

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.27

Mutation Taster

=14/86

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over