chr7-92070953-T-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.6556T>C(p.Ser2186Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,613,912 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. S2186C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 19 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.82

Publications

13 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=0.005694568).

BP6

Variant 7-92070953-T-C is Benign according to our data. Variant chr7-92070953-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AKAP9	NM_005751.5 link	c.6556T>C	p.Ser2186Pro	missense_variant	Exon 28 of 50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3 link	c.6532T>C	p.Ser2178Pro	missense_variant	Exon 28 of 50		NP_671714.1
AKAP9	NM_001379277.1 link	c.1201T>C	p.Ser401Pro	missense_variant	Exon 7 of 29		NP_001366206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 link	c.6556T>C	p.Ser2186Pro	missense_variant	Exon 28 of 50	1	NM_005751.5	ENSP00000348573.3

Frequencies

GnomAD3 genomes

AF:

0.00247

AC:

376

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000787

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00728

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00374

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00333

AC:

837

AN:

251434

AF XY:

0.00345

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00707

Gnomad NFE exome

AF:

0.00492

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00366

AC:

5354

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

2680

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.000917

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.00227

AC:

196

AN:

86256

European-Finnish (FIN)

AF:

0.00762

AC:

407

AN:

53414

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00405

AC:

4503

AN:

1111950

Other (OTH)

AF:

0.00295

AC:

178

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

256

512

767

1023

1279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<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:

0.00247

AC:

375

AN:

152110

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41498

American (AMR)

AF:

0.000786

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00728

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00374

AC:

254

AN:

67988

Other (OTH)

AF:

0.00142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00343

Hom.:

Bravo

AF:

0.00202

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00377

AC:

458

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00365

EpiControl

AF:

0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 11, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AKAP9 c.6556T>C (p.Ser2186Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 251434 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 1000-fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Long QT Syndrome phenotype (3.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.6556T>C in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2) / likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AKAP9: BP4, BS2 -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Long QT syndrome 11

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome;C0878544:Cardiomyopathy

Benign:1

Apr 01, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Sep 07, 2018

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

0.073

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

.;T;T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.0057

T;T;T;T

MetaSVM

Benign

-0.94

PhyloP100

1.8

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.060

N;.;.;N

REVEL

Benign

0.058

Sift

Benign

0.28

T;.;.;T

Sift4G

Benign

0.79

.;T;.;T

Vest4

0.27

MVP

0.30

MPC

0.088

ClinPred

0.012

GERP RS

3.2

PromoterAI

0.022

Neutral

(source)

Varity_R

0.084

gMVP

0.17

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over