rs761276121

Positions:

• chr7-92038633-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005751.5(AKAP9):​c.4553G>A​(p.Ser1518Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1518G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1289753).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.4553G>A	p.Ser1518Asn	missense_variant	17/50	ENST00000356239.8
AKAP9	NM_147185.3	c.4553G>A	p.Ser1518Asn	missense_variant	17/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.4553G>A	p.Ser1518Asn	missense_variant	17/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000440 AC: 11 AN: 250134 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461238 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1518 of the AKAP9 protein (p.Ser1518Asn). 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 570376). This variant has not been reported in the literature in individuals affected with AKAP9-related conditions. This variant is present in population databases (rs761276121, gnomAD 0.03%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.0022
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.95	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.79	N;.;.;.
REVEL	Benign	0.060
Sift	Benign	0.052	T;.;.;.
Vest4		0.17
MVP		0.55
MPC		0.10
ClinPred		0.098	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761276121; hg19: chr7-91667947;