rs61757664

chr7-92097646-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.10459G>A(p.Glu3487Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000499 in 1,614,086 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (8 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 7.00

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]

CYP51A1 (HGNC:2649): (cytochrome P450 family 51 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein participates in the synthesis of cholesterol by catalyzing the removal of the 14alpha-methyl group from lanosterol. Homologous genes are found in all three eukaryotic phyla, fungi, plants, and animals, suggesting that this is one of the oldest cytochrome P450 genes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0323748).
• BP6: Variant 7-92097646-G-A is Benign according to our data. Variant chr7-92097646-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191526.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=6}. Variant chr7-92097646-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.10459G>A	p.Glu3487Lys	missense_variant	42/50	ENST00000356239.8
AKAP9	NM_147185.3	c.10435G>A	p.Glu3479Lys	missense_variant	42/50
AKAP9	NM_001379277.1	c.5104G>A	p.Glu1702Lys	missense_variant	21/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.10459G>A	p.Glu3487Lys	missense_variant	42/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152198 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000649 AC: 163 AN: 251340 Hom.: 1 AF XY: 0.000729 AC XY: 99 AN XY: 135838

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000722

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.000488 AC: 713 AN: 1461770 Hom.: 8 Cov.: 34 AF XY: 0.000543 AC XY: 395 AN XY: 727180

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000405

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152316 Hom.: 2 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74472

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000842 Hom.: 2

Bravo AF: 0.000582

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000535 AC: 65

EpiCase AF: 0.00109

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2020	This variant is associated with the following publications: (PMID: 30847666, 23861362) -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Long QT syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -

Long QT syndrome 11 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Dec 19, 2014

The heterozygous variant in the AKAP9 gene (c.10459G>A; p.Glu3487Lys) is considered a VUS as this specific variant has not been previously published in the literature but has been seen in 66 individuals in the ExAC database (out of 122834 screened at this position). The amino acid change is non-conservative while the position is conserved only in mammals while the nucleotide position is moderately conserved. -

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

Jan 16, 2024

Variant summary: AKAP9 c.10459G>A (p.Glu3487Lys) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 251340 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 195-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. c.10459G>A has been reported in the literature in individuals, without strong evidence for causality (Ghouse_2015, van Lint_2019). 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: 26159999, 30847666). ClinVar contains an entry for this variant (Variation ID: 191526). 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 06, 2019

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). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 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	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.032	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N;.;N
REVEL	Benign	0.16
Sift	Benign	0.058	T;.;D
Vest4		0.48
MVP		0.60
MPC		0.22
ClinPred		0.077	T
GERP RS		4.6
Varity_R		0.18
gMVP		0.24

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: rs61757664; hg19: chr7-91726960; COSMIC: COSV99050164; COSMIC: COSV99050164;