7-92017092-G-A

Position:

chr7-92017092-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005751.5(AKAP9):c.3827G>A(p.Arg1276Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00766 in 1,570,710 control chromosomes in the GnomAD database, including 65 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. R1276R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0070 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 57 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.541

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=0.0028244555).

BP6

Variant 7-92017092-G-A is Benign according to our data. Variant chr7-92017092-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 191552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92017092-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00701 (1066/152140) while in subpopulation EAS AF= 0.0235 (122/5188). AF 95% confidence interval is 0.0201. There are 8 homozygotes in gnomad4. There are 528 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1066 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5 linkuse as main transcript	c.3827G>A	p.Arg1276Gln	missense_variant	12/50	ENST00000356239.8
AKAP9	NM_147185.3 linkuse as main transcript	c.3827G>A	p.Arg1276Gln	missense_variant	12/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8 linkuse as main transcript	c.3827G>A	p.Arg1276Gln	missense_variant	12/50	1	NM_005751.5	P4	Q99996-2

Frequencies

GnomAD3 genomes

AF:

0.00702

AC:

1067

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00398

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00636

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.0237

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00701

Gnomad OTH

AF:

0.00958

GnomAD3 exomes

AF:

0.00930

AC:

2047

AN:

220076

Hom.:

AF XY:

0.0102

AC XY:

1209

AN XY:

118328

show subpopulations

Gnomad AFR exome

AF:

0.00420

Gnomad AMR exome

AF:

0.00286

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.0219

Gnomad SAS exome

AF:

0.0172

Gnomad FIN exome

AF:

0.00118

Gnomad NFE exome

AF:

0.00835

Gnomad OTH exome

AF:

0.00663

GnomAD4 exome

AF:

0.00773

AC:

10971

AN:

1418570

Hom.:

Cov.:

AF XY:

0.00816

AC XY:

5758

AN XY:

705376

show subpopulations

Gnomad4 AFR exome

AF:

0.00394

Gnomad4 AMR exome

AF:

0.00297

Gnomad4 ASJ exome

AF:

0.0202

Gnomad4 EAS exome

AF:

0.0206

Gnomad4 SAS exome

AF:

0.0164

Gnomad4 FIN exome

AF:

0.00148

Gnomad4 NFE exome

AF:

0.00681

Gnomad4 OTH exome

AF:

0.00965

GnomAD4 genome

AF:

0.00701

AC:

1066

AN:

152140

Hom.:

Cov.:

AF XY:

0.00710

AC XY:

528

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00397

Gnomad4 AMR

AF:

0.00635

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.0235

Gnomad4 SAS

AF:

0.0166

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00701

Gnomad4 OTH

AF:

0.00948

Alfa

AF:

0.00941

Hom.:

Bravo

AF:

0.00706

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00886

AC:

ExAC

AF:

0.00878

AC:

1059

Asia WGS

AF:

0.0250

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 08, 2020	Variant summary: AKAP9 c.3827G>A (p.Arg1276Gln) 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 0.0093 in 220076 control chromosomes in the gnomAD database, including 21 homozygotes. The observed variant frequency is approximately 2790 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. Four 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. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	Eurofins Ntd Llc (ga)	Aug 04, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30821013, 29177109, 26230511) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	AKAP9: BP4, BS1, BS2 -

Long QT syndrome 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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

Invitae

Jan 26, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 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

0.085

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Benign

0.22

.;.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.024

LIST_S2

Uncertain

0.87

D;D;D;D

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.030

N;.;.;.

REVEL

Benign

0.014

Sift

Benign

0.60

T;.;.;.

Sift4G

Benign

0.94

.;T;T;.

Vest4

0.11

MVP

0.072

MPC

0.062

ClinPred

0.000025

GERP RS

-1.9

Varity_R

0.021

gMVP

0.057

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