rs141856443

Positions:

chr7-92102769-G-A

Variant summary

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

The NM_005751.5(AKAP9):c.11273G>A(p.Arg3758His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,176 control chromosomes in the GnomAD database, including 8 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. R3758C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0017 ( 7 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.14

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 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=0.0048562586).

BP6

Variant 7-92102769-G-A is Benign according to our data. Variant chr7-92102769-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 191531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92102769-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 237 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AKAP9	NM_005751.5 linkuse as main transcript	c.11273G>A	p.Arg3758His	missense_variant	46/50	ENST00000356239.8
AKAP9	NM_147185.3 linkuse as main transcript	c.11249G>A	p.Arg3750His	missense_variant	46/50
AKAP9	NM_001379277.1 linkuse as main transcript	c.5918G>A	p.Arg1973His	missense_variant	25/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8 linkuse as main transcript	c.11273G>A	p.Arg3758His	missense_variant	46/50	1	NM_005751.5	P4	Q99996-2

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

237

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00698

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00176

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00170

AC:

426

AN:

251302

Hom.:

AF XY:

0.00174

AC XY:

236

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00550

Gnomad NFE exome

AF:

0.00228

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00166

AC:

2423

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1202

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00474

Gnomad4 NFE exome

AF:

0.00182

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00156

AC:

237

AN:

152286

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00698

Gnomad4 NFE

AF:

0.00176

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.00125

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00156

AC:

189

EpiCase

AF:

0.00207

EpiControl

AF:

0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2023	- -
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+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Long QT syndrome 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Amyloidosis;C0007193:Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 30, 2018

- -

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

Feb 03, 2019

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

0.070

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.30

.;T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.85

D;D;T

M_CAP

Benign

0.0090

MetaRNN

Benign

0.0049

T;T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

0.55

N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.8

N;.;N

REVEL

Benign

0.018

Sift

Benign

0.43

T;.;T

Sift4G

Benign

0.45

.;.;T

Vest4

0.27

MVP

0.18

MPC

0.068

ClinPred

0.019

GERP RS

2.6

Varity_R

0.023

gMVP

0.14

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