rs34370932

chr7-92002699-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005751.5(AKAP9):c.2782T>C(p.Leu928=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,613,438 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (79 hom.)
• Consequence: AKAP9 NM_005751.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.947

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 7-92002699-T-C is Benign according to our data. Variant chr7-92002699-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 263768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92002699-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.947 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.2782T>C	p.Leu928=	synonymous_variant	8/50	ENST00000356239.8
AKAP9	NM_147185.3	c.2782T>C	p.Leu928=	synonymous_variant	8/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.2782T>C	p.Leu928=	synonymous_variant	8/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2176 AN: 151894 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00388 AC: 969 AN: 250002 Hom.: 25 AF XY: 0.00293 AC XY: 397 AN XY: 135338

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00166 AC: 2422 AN: 1461426 Hom.: 79 Cov.: 35 AF XY: 0.00147 AC XY: 1067 AN XY: 727010

Gnomad4 AFR exome AF: 0.0527

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.00434

GnomAD4 genome AF: 0.0144 AC: 2193 AN: 152012 Hom.: 47 Cov.: 32 AF XY: 0.0138 AC XY: 1023 AN XY: 74322

Gnomad4 AFR AF: 0.0494

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000486

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00323 Hom.: 16

Bravo AF: 0.0163

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 15, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Jan 26, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 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
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.16
Dann	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34370932; hg19: chr7-91632013;