rs76177450

chr7-92070953-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005751.5(AKAP9):c.6556T>C(p.Ser2186Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,613,912 control chromosomes in the GnomAD database, including 20 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2186C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (19 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.82

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005694568).
• BP6: Variant 7-92070953-T-C is Benign according to our data. Variant chr7-92070953-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 191520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92070953-T-C is described in Lovd as [Benign]. Variant chr7-92070953-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 376 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.6556T>C	p.Ser2186Pro	missense_variant	28/50	ENST00000356239.8
AKAP9	NM_147185.3	c.6532T>C	p.Ser2178Pro	missense_variant	28/50
AKAP9	NM_001379277.1	c.1201T>C	p.Ser401Pro	missense_variant	7/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.6556T>C	p.Ser2186Pro	missense_variant	28/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 151994 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00728

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00374

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00333 AC: 837 AN: 251434 Hom.: 2 AF XY: 0.00345 AC XY: 469 AN XY: 135890

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.00707

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00366 AC: 5354 AN: 1461802 Hom.: 19 Cov.: 31 AF XY: 0.00369 AC XY: 2680 AN XY: 727206

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00227

Gnomad4 FIN exome AF: 0.00762

Gnomad4 NFE exome AF: 0.00405

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00247 AC: 375 AN: 152110 Hom.: 1 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74368

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00728

Gnomad4 NFE AF: 0.00374

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00336 Hom.: 2

Bravo AF: 0.00202

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00377 AC: 458

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2021	Variant summary: AKAP9 c.6556T>C (p.Ser2186Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 251434 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 1000-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. To our knowledge, no occurrence of c.6556T>C in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2) / likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -

Long QT syndrome 11 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	AKAP9: BP4, BS2 -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Long QT syndrome;C0878544:Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 01, 2019

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2018

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	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	23
Dann	Uncertain	0.98
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.0057	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.91	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.060	N;.;.;N
REVEL	Benign	0.058
Sift	Benign	0.28	T;.;.;T
Vest4		0.27
MVP		0.30
MPC		0.088
ClinPred		0.012	T
GERP RS		3.2
Varity_R		0.084
gMVP		0.17

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: rs76177450; hg19: chr7-91700267;