7-92070953-T-C

Position:

chr7-92070953-T-C

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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. 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

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=0.005694568).

BP6

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

BS2

High AC in GnomAd4 at 375 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AKAP9	NM_005751.5 linkuse as main transcript	c.6556T>C	p.Ser2186Pro	missense_variant	28/50	ENST00000356239.8
AKAP9	NM_147185.3 linkuse as main transcript	c.6532T>C	p.Ser2178Pro	missense_variant	28/50
AKAP9	NM_001379277.1 linkuse as main transcript	c.1201T>C	p.Ser401Pro	missense_variant	7/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8 linkuse as main transcript	c.6556T>C	p.Ser2186Pro	missense_variant	28/50	1	NM_005751.5	P4	Q99996-2

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

GnomAD3 exomes

AF:

0.00333

AC:

837

AN:

251434

Hom.:

AF XY:

0.00345

AC XY:

469

AN XY:

135890

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 SAS exome

AF:

0.00209

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

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00227

Gnomad4 FIN exome

AF:

0.00762

Gnomad4 NFE exome

AF:

0.00405

Gnomad4 OTH exome

AF:

0.00295

GnomAD4 genome

AF:

0.00247

AC:

375

AN:

152110

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.000786

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00728

Gnomad4 NFE

AF:

0.00374

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00336

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2021	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. -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	AKAP9: BP4, BS2 -

Long QT syndrome 11

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

Long QT syndrome;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

Apr 01, 2019

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2018

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

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

MutationTaster

Benign

0.91

N;N;N

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

Varity_R

0.084

gMVP

0.17

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