rs2230768

chr7-92040822-G-Achr7-92040822-G-C

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.4841G>A(p.Arg1614Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,748 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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. R1614W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0078 (15 hom., cov: 31)
  • Exomes 𝑓: 0.00070 (16 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.527

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=0.0024280548).
• BP6: Variant 7-92040822-G-A is Benign according to our data. Variant chr7-92040822-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92040822-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00778 (1182/151938) while in subpopulation AFR AF= 0.0272 (1127/41440). AF 95% confidence interval is 0.0259. There are 15 homozygotes in gnomad4. There are 516 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1180 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.4841G>A	p.Arg1614Gln	missense_variant	18/50	ENST00000356239.8
AKAP9	NM_147185.3	c.4841G>A	p.Arg1614Gln	missense_variant	18/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.4841G>A	p.Arg1614Gln	missense_variant	18/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.00777 AC: 1180 AN: 151822 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00576

GnomAD3 exomes AF: 0.00186 AC: 467 AN: 251238 Hom.: 6 AF XY: 0.00122 AC XY: 166 AN XY: 135778

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000704 AC: 1029 AN: 1461810 Hom.: 16 Cov.: 34 AF XY: 0.000611 AC XY: 444 AN XY: 727200

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00778 AC: 1182 AN: 151938 Hom.: 15 Cov.: 31 AF XY: 0.00695 AC XY: 516 AN XY: 74256

Gnomad4 AFR AF: 0.0272

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00570

Alfa AF: 0.00131 Hom.: 4

Bravo AF: 0.00852

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2012	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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2021	Variant summary: AKAP9 c.4841G>A (p.Arg1614Gln) results in a conservative amino acid change in 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 0.0019 in 251238 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 558 fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Long QT Syndrome phenotype (3.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4841G>A in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. 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:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

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 15, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2016

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	0.096
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	18
Dann	Benign	0.92
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.88	D;D;D;D
MetaRNN	Benign	0.0024	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.13	N;.;.;.
REVEL	Benign	0.021
Sift	Benign	0.61	T;.;.;.
Vest4		0.10
MVP		0.17
MPC		0.066
ClinPred		0.00040	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.051

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: rs2230768; hg19: chr7-91670136;