rs10228334

Variant names:

• chr7-92084658-C-T
• rs10228334
• NM_005751.5:c.8665C>T
• AKAP9 p.Leu2889Leu

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005751.5(AKAP9):​c.8665C>T​(p.Leu2889Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,603,034 control chromosomes in the GnomAD database, including 123,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13549 hom., cov: 32)
  • Exomes 𝑓: 0.39 (110283 hom.)
• Consequence: AKAP9 NM_005751.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0130
• Publications: 32 publications found

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]

AKAP9 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
• long QT syndrome 11

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-92084658-C-T is Benign according to our data. Variant chr7-92084658-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.013 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005751.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	NM_005751.5	MANE Select	c.8665C>T	p.Leu2889Leu	synonymous	Exon 34 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.8641C>T	p.Leu2881Leu	synonymous	Exon 34 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.3310C>T	p.Leu1104Leu	synonymous	Exon 13 of 29	NP_001366206.1	A0A2R8Y590

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.8665C>T	p.Leu2889Leu	synonymous	Exon 34 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.3310C>T	p.Leu1104Leu	synonymous	Exon 13 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000394534.7	TSL:1	c.2158C>T	p.Leu720Leu	synonymous	Exon 7 of 23	ENSP00000378042.3	H7BYL6

Frequencies

GnomAD3 genomes AF: 0.415 AC: 63008 AN: 151840 Hom.: 13531 Cov.: 32

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.423

GnomAD2 exomes AF: 0.378 AC: 94441 AN: 250064 AF XY: 0.379

Gnomad AFR exome AF: 0.517

Gnomad AMR exome AF: 0.310

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.170

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.392

GnomAD4 exome AF: 0.385 AC: 559267 AN: 1451076 Hom.: 110283 Cov.: 32 AF XY: 0.386 AC XY: 278704 AN XY: 722482

African (AFR) AF: 0.518 AC: 17183 AN: 33202

American (AMR) AF: 0.315 AC: 14056 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 14126 AN: 26048

East Asian (EAS) AF: 0.184 AC: 7297 AN: 39568

South Asian (SAS) AF: 0.389 AC: 33315 AN: 85740

European-Finnish (FIN) AF: 0.387 AC: 20624 AN: 53348

Middle Eastern (MID) AF: 0.424 AC: 2385 AN: 5628

European-Non Finnish (NFE) AF: 0.387 AC: 426789 AN: 1102954

Other (OTH) AF: 0.391 AC: 23492 AN: 60008

GnomAD4 genome AF: 0.415 AC: 63078 AN: 151958 Hom.: 13549 Cov.: 32 AF XY: 0.412 AC XY: 30610 AN XY: 74264

African (AFR) AF: 0.514 AC: 21315 AN: 41438

American (AMR) AF: 0.361 AC: 5509 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1891 AN: 3470

East Asian (EAS) AF: 0.175 AC: 906 AN: 5188

South Asian (SAS) AF: 0.387 AC: 1865 AN: 4820

European-Finnish (FIN) AF: 0.387 AC: 4069 AN: 10526

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.387 AC: 26302 AN: 67942

Other (OTH) AF: 0.423 AC: 893 AN: 2112

Alfa AF: 0.408 Hom.: 21057

Bravo AF: 0.417

Asia WGS AF: 0.313 AC: 1086 AN: 3466

EpiCase AF: 0.392

EpiControl AF: 0.402

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Long QT syndrome 11 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.88
DANN	Benign	0.44
PhyloP100		-0.013
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10228334;

hg19: chr7-91713972;

COSMIC: COSV62341602;