NM_005751.5:c.4004_4006dupAAC

Variant names:

• chr7-92022864-A-AAAC
• rs10644111
• NM_005751.5:c.4004_4006dupAAC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_005751.5(AKAP9):​c.4004_4006dupAAC​(p.Lys1335_Leu1336insGln) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,603,344 control chromosomes in the GnomAD database, including 129,701 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16438 hom., cov: 0)
  • Exomes 𝑓: 0.39 (113263 hom.)
• Consequence: AKAP9 NM_005751.5 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.00
• Publications: 30 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005751.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 7-92022864-A-AAAC is Benign according to our data. Variant chr7-92022864-A-AAAC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 190508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.625 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.4004_4006dupAAC	p.Lys1335_Leu1336insGln	disruptive_inframe_insertion	Exon 14 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.4004_4006dupAAC	p.Lys1335_Leu1336insGln	disruptive_inframe_insertion	Exon 14 of 50	NP_671714.1	Q99996-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.4004_4006dupAAC	p.Lys1335_Leu1336insGln	disruptive_inframe_insertion	Exon 14 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000359028.7	TSL:5	c.4004_4006dupAAC	p.Lys1335_Leu1336insGln	disruptive_inframe_insertion	Exon 14 of 51	ENSP00000351922.4	A0A0A0MRF6
	AKAP9	ENST00000681412.1		c.4004_4006dupAAC	p.Lys1335_Leu1336insGln	disruptive_inframe_insertion	Exon 14 of 49	ENSP00000506486.1	A0A7P0TBH8

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68175 AN: 151718 Hom.: 16402 Cov.: 0

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.450

GnomAD2 exomes AF: 0.390 AC: 97595 AN: 250214 AF XY: 0.390

Gnomad AFR exome AF: 0.637

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.192

Gnomad FIN exome AF: 0.391

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.389 AC: 565279 AN: 1451508 Hom.: 113263 Cov.: 32 AF XY: 0.390 AC XY: 281644 AN XY: 722602

African (AFR) AF: 0.639 AC: 21200 AN: 33152

American (AMR) AF: 0.322 AC: 14344 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 14112 AN: 26050

East Asian (EAS) AF: 0.205 AC: 8116 AN: 39610

South Asian (SAS) AF: 0.404 AC: 34751 AN: 85990

European-Finnish (FIN) AF: 0.386 AC: 20563 AN: 53224

Middle Eastern (MID) AF: 0.432 AC: 2481 AN: 5746

European-Non Finnish (NFE) AF: 0.386 AC: 425599 AN: 1103072

Other (OTH) AF: 0.402 AC: 24113 AN: 60050

GnomAD4 genome AF: 0.450 AC: 68269 AN: 151836 Hom.: 16438 Cov.: 0 AF XY: 0.447 AC XY: 33145 AN XY: 74224

African (AFR) AF: 0.631 AC: 26092 AN: 41332

American (AMR) AF: 0.375 AC: 5726 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1886 AN: 3466

East Asian (EAS) AF: 0.197 AC: 1019 AN: 5168

South Asian (SAS) AF: 0.402 AC: 1940 AN: 4820

European-Finnish (FIN) AF: 0.384 AC: 4050 AN: 10548

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

European-Non Finnish (NFE) AF: 0.387 AC: 26283 AN: 67916

Other (OTH) AF: 0.449 AC: 945 AN: 2104

Alfa AF: 0.430 Hom.: 2618

Bravo AF: 0.456

Asia WGS AF: 0.347 AC: 1210 AN: 3478

EpiCase AF: 0.393

EpiControl AF: 0.401

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Cardiovascular phenotype (2)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 11 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10644111; hg19: chr7-91652178; COSMIC: COSV62337888;