rs6964587

Positions:

chr7-92001306-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005751.5(AKAP9):c.1389G>T(p.Met463Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,613,566 control chromosomes in the GnomAD database, including 124,558 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 Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13467 hom., cov: 32)

Exomes 𝑓: 0.39 ( 111091 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.232

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.2644082E-5).

BP6

Variant 7-92001306-G-T is Benign according to our data. Variant chr7-92001306-G-T is described in ClinVar as [Benign]. Clinvar id is 136347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92001306-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP9	NM_005751.5 link	c.1389G>T	p.Met463Ile	missense_variant	8/50	ENST00000356239.8	NP_005742.4	Q99996-2Q6PJH3Q5GIA7
AKAP9	NM_147185.3 link	c.1389G>T	p.Met463Ile	missense_variant	8/50		NP_671714.1	Q99996-3Q6PJH3Q5GIA7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 link	c.1389G>T	p.Met463Ile	missense_variant	8/50	1	NM_005751.5	ENSP00000348573.3		Q99996-2

Frequencies

GnomAD3 genomes

AF:

0.414

AC:

62827

AN:

151854

Hom.:

13449

Cov.:

show subpopulations

Gnomad AFR

AF:

0.510

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.362

Gnomad ASJ

AF:

0.545

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.387

Gnomad MID

AF:

0.383

Gnomad NFE

AF:

0.387

Gnomad OTH

AF:

0.424

GnomAD3 exomes

AF:

0.378

AC:

94765

AN:

250610

Hom.:

18740

AF XY:

0.380

AC XY:

51511

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.512

Gnomad AMR exome

AF:

0.311

Gnomad ASJ exome

AF:

0.547

Gnomad EAS exome

AF:

0.170

Gnomad SAS exome

AF:

0.391

Gnomad FIN exome

AF:

0.392

Gnomad NFE exome

AF:

0.391

Gnomad OTH exome

AF:

0.394

GnomAD4 exome

AF:

0.387

AC:

564993

AN:

1461594

Hom.:

111091

Cov.:

AF XY:

0.387

AC XY:

281183

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.513

Gnomad4 AMR exome

AF:

0.316

Gnomad4 ASJ exome

AF:

0.543

Gnomad4 EAS exome

AF:

0.184

Gnomad4 SAS exome

AF:

0.389

Gnomad4 FIN exome

AF:

0.387

Gnomad4 NFE exome

AF:

0.388

Gnomad4 OTH exome

AF:

0.392

GnomAD4 genome

AF:

0.414

AC:

62896

AN:

151972

Hom.:

13467

Cov.:

AF XY:

0.411

AC XY:

30510

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.510

Gnomad4 AMR

AF:

0.361

Gnomad4 ASJ

AF:

0.545

Gnomad4 EAS

AF:

0.174

Gnomad4 SAS

AF:

0.387

Gnomad4 FIN

AF:

0.387

Gnomad4 NFE

AF:

0.387

Gnomad4 OTH

AF:

0.423

Alfa

AF:

0.399

Hom.:

26941

Bravo

AF:

0.416

TwinsUK

AF:

0.378

AC:

1400

ALSPAC

AF:

0.392

AC:

1510

ESP6500AA

AF:

0.514

AC:

2261

ESP6500EA

AF:

0.403

AC:

3466

ExAC

AF:

0.382

AC:

46412

Asia WGS

AF:

0.314

AC:

1095

AN:

3478

EpiCase

AF:

0.392

EpiControl

AF:

0.403

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2011	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 5727/13002=44% -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2019	Variant summary: AKAP9 c.1389G>T (p.Met463Ile) 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 0.38 in 250610 control chromosomes, predominantly at a frequency of 0.51 within the African or African-American subpopulation in the gnomAD database, including 2115 homozygotes. Therefore, suggesting the variant is the major allele found in population(s) of African American origin. Four ClinVar submissions (evaluation after 2014) cite the variant three times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2015	- -

Long QT syndrome 11

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Colorectal cancer

Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 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

0.14

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.6

DANN

Benign

0.37

DEOGEN2

Benign

0.28

.;.;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.32

T;T;T;T

MetaRNN

Benign

0.000043

T;T;T;T

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.69

N;.;.;.

REVEL

Benign

0.036

Sift

Benign

0.064

T;.;.;.

Sift4G

Benign

0.067

.;T;T;.

Vest4

0.098

MPC

0.057

ClinPred

0.0019

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.057

gMVP

0.075

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

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