rs151021935

chr7-92052726-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005751.5(AKAP9):c.5369T>G(p.Val1790Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,600,608 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (17 hom.)
• Consequence: AKAP9 NM_005751.5 missense, splice_region
• Scores: Splicing: ADA: 0.00001323
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 1.28

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068029463).
• BP6: Variant 7-92052726-T-G is Benign according to our data. Variant chr7-92052726-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180263.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=2, Uncertain_significance=1}. Variant chr7-92052726-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000723 (1047/1448314) while in subpopulation MID AF= 0.0287 (165/5748). AF 95% confidence interval is 0.0251. There are 17 homozygotes in gnomad4_exome. There are 522 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd at 141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.5369T>G	p.Val1790Gly	missense_variant, splice_region_variant	22/50	ENST00000356239.8
AKAP9	NM_147185.3	c.5369T>G	p.Val1790Gly	missense_variant, splice_region_variant	22/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.5369T>G	p.Val1790Gly	missense_variant, splice_region_variant	22/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152176 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000919 AC: 230 AN: 250160 Hom.: 0 AF XY: 0.000961 AC XY: 130 AN XY: 135262

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000721

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000823

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.000723 AC: 1047 AN: 1448314 Hom.: 17 Cov.: 28 AF XY: 0.000724 AC XY: 522 AN XY: 721424

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000768

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.000477

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152294 Hom.: 2 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74484

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00143 Hom.: 4

Bravo AF: 0.00107

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00131

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AKAP9: BP4, BS1, BS2 -
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	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Long QT syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: BS1, BP4 -

Congenital long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Sudden cardiac death Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 30, 2014

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2016

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. -

Long QT syndrome 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 03, 2020

- -

AKAP9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2018

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	0.071
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	14
Dann	Benign	0.75
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.19	N;.;.
REVEL	Benign	0.13
Sift	Benign	0.48	T;.;.
Vest4		0.35
MVP		0.24
MPC		0.066
ClinPred		0.011	T
GERP RS		2.5
Varity_R		0.029
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.062
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

Other links and lift over

dbSNP: rs151021935; hg19: chr7-91682040;