rs61757672

chr7-92079408-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005751.5(AKAP9):c.7275G>A(p.Gln2425=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00476 in 1,614,020 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (28 hom.)
• Consequence: AKAP9 NM_005751.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.108

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-92079408-G-A is Benign according to our data. Variant chr7-92079408-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92079408-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.108 with no splicing effect.
• BS2: High AC in GnomAd at 445 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.7275G>A	p.Gln2425=	synonymous_variant	31/50	ENST00000356239.8
AKAP9	NM_147185.3	c.7251G>A	p.Gln2417=	synonymous_variant	31/50
AKAP9	NM_001379277.1	c.1920G>A	p.Gln640=	synonymous_variant	10/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.7275G>A	p.Gln2425=	synonymous_variant	31/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 445 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00460

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00300 AC: 751 AN: 250514 Hom.: 3 AF XY: 0.00304 AC XY: 412 AN XY: 135600

Gnomad AFR exome AF: 0.000998

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00627

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00424

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00496 AC: 7244 AN: 1461716 Hom.: 28 Cov.: 32 AF XY: 0.00479 AC XY: 3485 AN XY: 727140

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00624

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.00277

Gnomad4 NFE exome AF: 0.00575

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.00292 AC: 444 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74474

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.00460

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00439 Hom.: 3

Bravo AF: 0.00293

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00385

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Jan 06, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Long QT syndrome 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

AKAP9: BP4, BP7, BS2 -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2015

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
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.3
Dann	Benign	0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61757672; hg19: chr7-91708722; COSMIC: COSV62343634; COSMIC: COSV62343634;