7-92099813-A-G

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.10840A>G(p.Met3614Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00942 in 1,614,124 control chromosomes in the GnomAD database, including 101 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. M3614K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0090 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 93 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.90

Publications

16 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 links:

CYP51A1 (HGNC:2649): (cytochrome P450 family 51 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein participates in the synthesis of cholesterol by catalyzing the removal of the 14alpha-methyl group from lanosterol. Homologous genes are found in all three eukaryotic phyla, fungi, plants, and animals, suggesting that this is one of the oldest cytochrome P450 genes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

CYP51A1 Gene-Disease associations (from GenCC):

cataract
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

CYP51A1 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=0.0056039095).

BP6

Variant 7-92099813-A-G is Benign according to our data. Variant chr7-92099813-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP9	NM_005751.5 link	c.10840A>G	p.Met3614Val	missense_variant	Exon 44 of 50	ENST00000356239.8	NP_005742.4	Q99996-2Q6PJH3Q5GIA7
AKAP9	NM_147185.3 link	c.10816A>G	p.Met3606Val	missense_variant	Exon 44 of 50		NP_671714.1	Q99996-3Q6PJH3Q5GIA7
AKAP9	NM_001379277.1 link	c.5485A>G	p.Met1829Val	missense_variant	Exon 23 of 29		NP_001366206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 link	c.10840A>G	p.Met3614Val	missense_variant	Exon 44 of 50	1	NM_005751.5	ENSP00000348573.3		Q99996-2

Frequencies

GnomAD3 genomes

AF:

0.00905

AC:

1378

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00854

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.00703

AC:

1767

AN:

251372

AF XY:

0.00721

show subpopulations

Gnomad AFR exome

AF:

0.00892

Gnomad AMR exome

AF:

0.00543

Gnomad ASJ exome

AF:

0.00903

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.00930

GnomAD4 exome

AF:

0.00945

AC:

13819

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00945

AC XY:

6870

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00732

AC:

245

AN:

33478

American (AMR)

AF:

0.00572

AC:

256

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00930

AC:

243

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00281

AC:

242

AN:

86256

European-Finnish (FIN)

AF:

0.00144

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0109

AC:

12141

AN:

1111942

Other (OTH)

AF:

0.00916

AC:

553

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

775

1550

2324

3099

3874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.00905

AC:

1378

AN:

152324

Hom.:

Cov.:

AF XY:

0.00831

AC XY:

619

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00851

AC:

354

AN:

41580

American (AMR)

AF:

0.0111

AC:

170

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0111

AC:

755

AN:

68036

Other (OTH)

AF:

0.0171

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

140

210

280

350

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:

0.0101

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.00884

AC:

ExAC

AF:

0.00717

AC:

871

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00992

EpiControl

AF:

0.0122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Oct 08, 2019

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.10840A>G (p.Met3614Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.007 in 251372 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 703 fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. 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/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Jul 11, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Long QT syndrome 11

Benign:2

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AKAP9: BP4, BS1, BS2; CYP51A1: BS1, BS2 -

Cardiomyopathy

Benign:1

Jun 04, 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

- -

Congenital long QT syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 10, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

0.12

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.32

.;T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.63

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

T;T;T

MetaRNN

Benign

0.0056

T;T;T

MetaSVM

Benign

-0.90

PhyloP100

2.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

N;.;N

REVEL

Benign

0.042

Sift

Benign

0.27

T;.;T

Sift4G

Benign

0.45

.;.;T

Vest4

0.28

MVP

0.21

MPC

0.080

ClinPred

0.014

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.16

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over