7-92084649-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005751.5(AKAP9):c.8656A>G(p.Ile2886Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,608,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2886L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -3.71

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01799485).
• BP6: Variant 7-92084649-A-G is Benign according to our data. Variant chr7-92084649-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 222489.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr7-92084649-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.8656A>G	p.Ile2886Val	missense_variant	34/50	ENST00000356239.8
AKAP9	NM_147185.3	c.8632A>G	p.Ile2878Val	missense_variant	34/50
AKAP9	NM_001379277.1	c.3301A>G	p.Ile1101Val	missense_variant	13/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.8656A>G	p.Ile2886Val	missense_variant	34/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000188 AC: 47 AN: 250340 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135474

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000373 AC: 543 AN: 1456674 Hom.: 0 Cov.: 28 AF XY: 0.000338 AC XY: 245 AN XY: 724842

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000462

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74348

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.0000546

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2023	Variant summary: AKAP9 c.8656A>G (p.Ile2886Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 282002 control chromosomes (gnomAD, Le Scouarnec_2015), predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 99 fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Long QT Syndrome (3.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.8656A>G has been reported in the literature in individuals affected with Brugada Syndrome as well as in asymptomatic individuals (Allegue_2015, Campuzano_2019). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26230511, 30821013, 25650408). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2886 of the AKAP9 protein (p.Ile2886Val). This variant is present in population databases (rs143283097, gnomAD 0.03%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26230511). ClinVar contains an entry for this variant (Variation ID: 222489). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2019

This alteration is classified as likely 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	0.058
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.0010
Dann	Benign	0.19
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.53	D;D;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.13	N;.;N
REVEL	Benign	0.031
Sift	Benign	0.54	T;.;T
Vest4		0.029
MVP		0.12
MPC		0.047
ClinPred		0.012	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.015
gMVP		0.058

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: rs143283097; hg19: chr7-91713963;