rs9785013

chr7-92044988-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005751.5(AKAP9):c.5163-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,570,554 control chromosomes in the GnomAD database, including 128,766 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16898 hom., cov: 32)
  • Exomes 𝑓: 0.39 (111868 hom.)
• Consequence: AKAP9 NM_005751.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.431

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 7-92044988-G-A is Benign according to our data. Variant chr7-92044988-G-A is described in ClinVar as [Benign]. Clinvar id is 136331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92044988-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.5163-20G>A		intron_variant		ENST00000356239.8
AKAP9	NM_147185.3	c.5163-20G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.5163-20G>A		intron_variant		1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68922 AN: 151872 Hom.: 16861 Cov.: 32

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.452

GnomAD3 exomes AF: 0.391 AC: 97948 AN: 250218 Hom.: 20351 AF XY: 0.391 AC XY: 52930 AN XY: 135374

Gnomad AFR exome AF: 0.650

Gnomad AMR exome AF: 0.317

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.193

Gnomad SAS exome AF: 0.408

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.392 AC: 556095 AN: 1418564 Hom.: 111868 Cov.: 27 AF XY: 0.392 AC XY: 277698 AN XY: 708534

Gnomad4 AFR exome AF: 0.655

Gnomad4 AMR exome AF: 0.323

Gnomad4 ASJ exome AF: 0.543

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.404

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.389

Gnomad4 OTH exome AF: 0.404

GnomAD4 genome AF: 0.454 AC: 69017 AN: 151990 Hom.: 16898 Cov.: 32 AF XY: 0.451 AC XY: 33511 AN XY: 74270

Gnomad4 AFR AF: 0.644

Gnomad4 AMR AF: 0.377

Gnomad4 ASJ AF: 0.545

Gnomad4 EAS AF: 0.198

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.387

Gnomad4 OTH AF: 0.451

Alfa AF: 0.412 Hom.: 15140

Bravo AF: 0.460

Asia WGS AF: 0.349 AC: 1216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2019	Variant summary: AKAP9 c.5163-20G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.39 in 250218 control chromosomes, predominantly at a frequency of 0.65 within the African or African-American subpopulation in the gnomAD database, including 3362 homozygotes. Therefore, suggesting the variant is the major allele observed in population(s) of African-American origin. A ClinVar submission (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2011	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Long QT syndrome 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	1.8
Dann	Benign	0.34

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

Other links and lift over

dbSNP: rs9785013; hg19: chr7-91674302; COSMIC: COSV62348317; COSMIC: COSV62348317;