rs60031334

chr7-92001218-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005751.5(AKAP9):c.1301G>A(p.Arg434Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00215 in 1,613,888 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R434W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (22 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.91

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 (MetaRNN=0.0029833019).
• BP6: Variant 7-92001218-G-A is Benign according to our data. Variant chr7-92001218-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 191550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92001218-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1758/152164) while in subpopulation AFR AF= 0.0399 (1656/41524). AF 95% confidence interval is 0.0383. There are 35 homozygotes in gnomad4. There are 860 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1757 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.1301G>A	p.Arg434Gln	missense_variant	8/50	ENST00000356239.8
AKAP9	NM_147185.3	c.1301G>A	p.Arg434Gln	missense_variant	8/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.1301G>A	p.Arg434Gln	missense_variant	8/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1757 AN: 152046 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00284 AC: 711 AN: 250028 Hom.: 15 AF XY: 0.00230 AC XY: 311 AN XY: 135258

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00117 AC: 1711 AN: 1461724 Hom.: 22 Cov.: 31 AF XY: 0.00101 AC XY: 734 AN XY: 727146

Gnomad4 AFR exome AF: 0.0406

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.0116 AC: 1758 AN: 152164 Hom.: 35 Cov.: 33 AF XY: 0.0116 AC XY: 860 AN XY: 74394

Gnomad4 AFR AF: 0.0399

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00244 Hom.: 4

Bravo AF: 0.0131

ESP6500AA AF: 0.0295 AC: 130

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00357 AC: 433

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2019	Variant summary: AKAP9 c.1301G>A (p.Arg434Gln) results in a conservative amino acid change located in the ELK domain (IPR005539) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 250028 control chromosomes, predominantly at a frequency of 0.039 within the African or African-American subpopulation in the gnomAD database, including 14 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is well above the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1301G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x) /likely benign (1x). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Long QT syndrome 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Invitae

Jan 29, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 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
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	19
Dann	Uncertain	0.98
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.0063
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.57	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N;.;.;.
REVEL	Benign	0.091
Sift	Benign	0.47	T;.;.;.
Vest4		0.12
MVP		0.32
MPC		0.065
ClinPred		0.011	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.12

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: rs60031334; hg19: chr7-91630532;