chr7-92040795-C-T

Position:

chr7-92040795-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005751.5(AKAP9):c.4814C>T(p.Thr1605Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

AKAP9
NM_005751.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.89

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06115547).

BS2

High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP9	NM_005751.5 linkuse as main transcript	c.4814C>T	p.Thr1605Met	missense_variant	18/50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3 linkuse as main transcript	c.4814C>T	p.Thr1605Met	missense_variant	18/50		NP_671714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 linkuse as main transcript	c.4814C>T	p.Thr1605Met	missense_variant	18/50	1	NM_005751.5	ENSP00000348573	P4	Q99996-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151684

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251206

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151684

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74030

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 01, 2017	Testing was performed at the Invitae laboratory. Given the weak gene-disease association, type of variant, and frequency in gnomAD, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence (CC Nov 2015): AKAP9 is a proposed long QT gene. Per Invitae, it has limited evidence as a long QT gene. Of note, there is only one AKAP9 variant in ClinVar classified as likely pathogenic or pathogenic by a clinical laboratory (Blueprint). ExAC constraint analyses of AKAP9 appears to be tolerant to missense variation (Z= -2.75), as well as loss of function/truncating variation (pLI=0.00). The variant has not been seen in any cases of ARVC or other inherited cardiovascular disease (per PubMed and Google). In silico analysis do not agree on the effect on protein function. The Thr is moderately conserved. The variant is reported in 14 of 138,374 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 14 of 9433 East Asian individuals (MAF = 0.07421%). There is good coverage at that site. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2023	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 190483). This variant has not been reported in the literature in individuals affected with AKAP9-related conditions. This variant is present in population databases (rs777627168, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1605 of the AKAP9 protein (p.Thr1605Met). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2021

The p.T1605M variant (also known as c.4814C>T), located in coding exon 18 of the AKAP9 gene, results from a C to T substitution at nucleotide position 4814. The threonine at codon 1605 is replaced by methionine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, methionine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.33

.;.;T;T

Eigen

Benign

0.048

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.061

T;T;T;T

MetaSVM

Benign

-0.93

MutationTaster

Benign

0.97

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.2

N;.;.;.

REVEL

Benign

0.058

Sift

Uncertain

0.0020

D;.;.;.

Sift4G

Uncertain

0.017

.;D;T;.

Vest4

0.16

MVP

0.39

MPC

0.15

ClinPred

0.17

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.068

gMVP

0.36

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