rs35669569

Positions:

chr7-91973801-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000356239.8(AKAP9):c.139C>T(p.His47Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,038 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H47H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0075 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 112 hom. )

Consequence

AKAP9
ENST00000356239.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.932

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006234467).

BP6

Variant 7-91973801-C-T is Benign according to our data. Variant chr7-91973801-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 191549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-91973801-C-T is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 1138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP9	NM_005751.5 linkuse as main transcript	c.139C>T	p.His47Tyr	missense_variant	2/50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3 linkuse as main transcript	c.139C>T	p.His47Tyr	missense_variant	2/50		NP_671714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 linkuse as main transcript	c.139C>T	p.His47Tyr	missense_variant	2/50	1	NM_005751.5	ENSP00000348573	P4	Q99996-2

Frequencies

GnomAD3 genomes

AF:

0.00748

AC:

1138

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00804

AC:

2021

AN:

251216

Hom.:

AF XY:

0.00770

AC XY:

1046

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.00335

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.0142

Gnomad NFE exome

AF:

0.0132

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.0112

AC:

16320

AN:

1461816

Hom.:

112

Cov.:

AF XY:

0.0107

AC XY:

7778

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.00380

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000452

Gnomad4 FIN exome

AF:

0.0140

Gnomad4 NFE exome

AF:

0.0132

Gnomad4 OTH exome

AF:

0.00926

GnomAD4 genome

AF:

0.00748

AC:

1138

AN:

152222

Hom.:

Cov.:

AF XY:

0.00736

AC XY:

548

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00229

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.0171

Gnomad4 NFE

AF:

0.0112

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.00702

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.00813

AC:

987

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0132

EpiControl

AF:

0.0118

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2020	Variant summary: AKAP9 c.139C>T (p.His47Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.008 in 251216 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 2413 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. Six 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. -

Long QT syndrome 11

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	AKAP9: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Congenital long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Atrial fibrillation;C0007194:Hypertrophic cardiomyopathy;C0018801:Heart failure;C0878544:Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 21, 2019

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2015

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

0.084

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Benign

0.32

.;.;T;T;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.66

T;T;T;T;T;T

MetaRNN

Benign

0.0062

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.98

N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.4

N;.;N;.;.;N

REVEL

Benign

0.054

Sift

Benign

0.23

T;.;T;.;.;T

Sift4G

Benign

0.21

.;T;T;T;.;T

Polyphen

0.0

.;.;B;.;.;.

Vest4

0.23

MVP

0.42

MPC

0.059

ClinPred

0.0053

GERP RS

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.037

gMVP

0.037

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over