rs139965373

chr7-92014296-G-A

Variant summary

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

The NM_005751.5(AKAP9):c.3580G>A(p.Ala1194Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000385 in 1,613,196 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. A1194G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: 3.76

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=0.010737747).
• BP6: Variant 7-92014296-G-A is Benign according to our data. Variant chr7-92014296-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180262.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=2}. Variant chr7-92014296-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.3580G>A	p.Ala1194Thr	missense_variant	10/50	ENST00000356239.8
AKAP9	NM_147185.3	c.3580G>A	p.Ala1194Thr	missense_variant	10/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.3580G>A	p.Ala1194Thr	missense_variant	10/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000605 AC: 152 AN: 251174 Hom.: 1 AF XY: 0.000648 AC XY: 88 AN XY: 135746

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000387 AC: 565 AN: 1460940 Hom.: 2 Cov.: 29 AF XY: 0.000421 AC XY: 306 AN XY: 726804

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00567

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000258

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000567

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 25, 2018	The AKAP9 c.3580G>A; p.Ala1194Thr variant (rs139965373, ClinVar variant ID 180262) has been detected in large whole-exome datasets from a cohort of SIDS patients (Neubauer 2017) and an unselected population (Ng 2013). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.06% (identified on 159 out of 276,956 chromosomes, including one homozygote). The alanine at position 1194 is highly conserved, considering 11 species, and computational analyses of the effects of the p.Ala1194Thr variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Ala1194Thr variant cannot be determined with certainty. -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AKAP9: BP4, BS1, BS2 -

Long QT syndrome 11 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Sep 30, 2015

- -

Congenital long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 18, 2019

Variant summary: AKAP9 c.3580G>A (p.Ala1194Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251174 control chromosomes, predominantly at a frequency of 0.00095 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 95 fold of 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 Latino origin. c.3580G>A has been reported in the literature in individuals affected with Sudden infant death syndrome, Hypertrophic Cardiomyopathy and prostate cancer (Neubauer_2017, Forleo_2017, Belic_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Additionally, co-occurrences with other pathogenic variants have been reported (MYBPC3 c.506-2A>C; BRCA2 c.4091_4092insAA, p.I1364fs) (Forleo_2017, Belic_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and uncertain significance (5x). Based on the evidence outlined above, the variant was classified as likely benign. -

AKAP9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ventricular fibrillation Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

May 26, 2014

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 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	0.15
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.85	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.10	T;.;.;.
Vest4		0.34
MVP		0.59
MPC		0.20
ClinPred		0.035	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139965373; hg19: chr7-91643610; COSMIC: COSV100662924;