rs6960867

chr7-92083384-A-Gchr7-92083384-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005751.5(AKAP9):c.8375A>G(p.Asn2792Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,613,262 control chromosomes in the GnomAD database, including 116,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. N2792H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (9247 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106878 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.334

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.6543946E-4).
• BP6: Variant 7-92083384-A-G is Benign according to our data. Variant chr7-92083384-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92083384-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.8375A>G	p.Asn2792Ser	missense_variant	33/50	ENST00000356239.8
AKAP9	NM_147185.3	c.8351A>G	p.Asn2784Ser	missense_variant	33/50
AKAP9	NM_001379277.1	c.3020A>G	p.Asn1007Ser	missense_variant	12/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.8375A>G	p.Asn2792Ser	missense_variant	33/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51609 AN: 151960 Hom.: 9249 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.369

GnomAD3 exomes AF: 0.359 AC: 89641 AN: 249908 Hom.: 16845 AF XY: 0.366 AC XY: 49453 AN XY: 135254

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.171

Gnomad SAS exome AF: 0.392

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.383

GnomAD4 exome AF: 0.379 AC: 553710 AN: 1461184 Hom.: 106878 Cov.: 42 AF XY: 0.380 AC XY: 276338 AN XY: 726924

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.301

Gnomad4 ASJ exome AF: 0.541

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.389

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.388

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.339 AC: 51620 AN: 152078 Hom.: 9247 Cov.: 32 AF XY: 0.339 AC XY: 25231 AN XY: 74346

Gnomad4 AFR AF: 0.251

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.543

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.385

Gnomad4 FIN AF: 0.386

Gnomad4 NFE AF: 0.386

Gnomad4 OTH AF: 0.368

Alfa AF: 0.381 Hom.: 19570

Bravo AF: 0.331

TwinsUK AF: 0.377 AC: 1397

ALSPAC AF: 0.392 AC: 1511

ESP6500AA AF: 0.268 AC: 1180

ESP6500EA AF: 0.401 AC: 3451

ExAC AF: 0.359 AC: 43538

Asia WGS AF: 0.294 AC: 1026 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.402

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Long QT syndrome 11 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2015

This alteration is classified as 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	0.071
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	7.0
Dann	Benign	0.81
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.77	T;T;T;T
MetaRNN	Benign	0.00057	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N;.;.;N
REVEL	Benign	0.070
Sift	Benign	0.23	T;.;.;T
Vest4		0.061
MPC		0.046
ClinPred		0.0056	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.078

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: rs6960867; hg19: chr7-91712698; COSMIC: COSV62339152; COSMIC: COSV62339152;