rs1063243

Positions:

• chr7-92097613-A-C
• chr7-92097613-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005751.5(AKAP9):​c.10426A>C​(p.Arg3476Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,613,192 control chromosomes in the GnomAD database, including 125,396 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13845 hom., cov: 32)
  • Exomes 𝑓: 0.39 (111551 hom.)
• Consequence: AKAP9 NM_005751.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.907

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]

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]

AKAP9 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-92097613-A-C is Benign according to our data. Variant chr7-92097613-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 136344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92097613-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.907 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP9	NM_005751.5	c.10426A>C	p.Arg3476Arg	synonymous_variant	42/50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3	c.10402A>C	p.Arg3468Arg	synonymous_variant	42/50		NP_671714.1
AKAP9	NM_001379277.1	c.5071A>C	p.Arg1691Arg	synonymous_variant	21/29		NP_001366206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8	c.10426A>C	p.Arg3476Arg	synonymous_variant	42/50	1	NM_005751.5	ENSP00000348573.3

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63548 AN: 151976 Hom.: 13826 Cov.: 32

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.425

GnomAD3 exomes AF: 0.380 AC: 95376 AN: 251212 Hom.: 19013 AF XY: 0.381 AC XY: 51750 AN XY: 135846

Gnomad AFR exome AF: 0.531

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.171

Gnomad SAS exome AF: 0.392

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.394

GnomAD4 exome AF: 0.387 AC: 565882 AN: 1461098 Hom.: 111551 Cov.: 47 AF XY: 0.387 AC XY: 281564 AN XY: 726868

Gnomad4 AFR exome AF: 0.531

Gnomad4 AMR exome AF: 0.317

Gnomad4 ASJ exome AF: 0.543

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.390

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.389

Gnomad4 OTH exome AF: 0.394

GnomAD4 genome AF: 0.418 AC: 63619 AN: 152094 Hom.: 13845 Cov.: 32 AF XY: 0.415 AC XY: 30875 AN XY: 74344

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.363

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.387

Gnomad4 OTH AF: 0.425

Alfa AF: 0.397 Hom.: 30802

Bravo AF: 0.422

Asia WGS AF: 0.316 AC: 1102 AN: 3478

EpiCase AF: 0.393

EpiControl AF: 0.403

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2019	- -
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	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 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	-0.75
CADD	Benign	8.9
DANN	Benign	0.53
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: rs1063243; hg19: chr7-91726927; COSMIC: COSV62342471; COSMIC: COSV62342471;