7-91941116-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005751.5(AKAP9):c.17G>A(p.Arg6Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.88

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2715356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.17G>A	p.Arg6Lys	missense_variant	1/50	ENST00000356239.8
AKAP9	NM_147185.3	c.17G>A	p.Arg6Lys	missense_variant	1/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.17G>A	p.Arg6Lys	missense_variant	1/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2022

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 6 of the AKAP9 protein (p.Arg6Lys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with AKAP9-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2021

The p.R6K variant (also known as c.17G>A), located in coding exon 1 of the AKAP9 gene, results from a G to A substitution at nucleotide position 17. The arginine at codon 6 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;T;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;.;.;.
MutationTaster	Benign	0.55	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N;.;N;N;N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;.;D;D;D
Polyphen		0.99	.;.;D;.;.
Vest4		0.63
MutPred		0.37		Gain of ubiquitination at R6 (P = 0.0155);Gain of ubiquitination at R6 (P = 0.0155);Gain of ubiquitination at R6 (P = 0.0155);Gain of ubiquitination at R6 (P = 0.0155);Gain of ubiquitination at R6 (P = 0.0155);
MVP		0.44
MPC		0.35
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.54
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-91570430;