rs397825978

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP9	NM_005751.5	c.4004_4006dupAAC	p.Lys1335_Leu1336insGln	disruptive_inframe_insertion	Exon 14 of 50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3	c.4004_4006dupAAC	p.Lys1335_Leu1336insGln	disruptive_inframe_insertion	Exon 14 of 50		NP_671714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8	c.4004_4006dupAAC	p.Lys1335_Leu1336insGln	disruptive_inframe_insertion	Exon 14 of 50	1	NM_005751.5	ENSP00000348573.3

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

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 08, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 30, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in dbSNP (all): 865/2184=40% -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 12, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AKAP9 c.4004_4006dupAAC (p.Lys1335_Leu1336insGln) results in an in-frame insertion that is predicted to insert Gln amino acid into the encoded protein. The variant allele was found at a frequency of 0.4 in 281434 control chromosomes, predominantly at a frequency of 0.63 within the African or African-American subpopulation in the gnomAD database, including 4942 homozygotes. Therefore, suggesting the variant is the major allele observed in population(s) of African-American origin. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times a benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:2

Sep 17, 2012

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 17, 2012

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome 11 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital long QT syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;