Genetic Variant AKAP9:c.4693-10A>T (chr7-92040664-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_005751.5(AKAP9):c.4693-10A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 23)

Exomes 𝑓: 0.00093 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AKAP9
NM_005751.5 intron

Scores

Splicing: ADA: 0.0002646

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.556

Publications

0 publications found

Variant links:

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

AKAP9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 7-92040664-A-T is Benign according to our data. Variant chr7-92040664-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 457103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP9	NM_005751.5 link	c.4693-10A>T		intron_variant	Intron 17 of 49	ENST00000356239.8	NP_005742.4	Q99996-2Q6PJH3Q5GIA7
AKAP9	NM_147185.3 link	c.4693-10A>T		intron_variant	Intron 17 of 49		NP_671714.1	Q99996-3Q6PJH3Q5GIA7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8 link	c.4693-10A>T		intron_variant	Intron 17 of 49	1	NM_005751.5	ENSP00000348573.3		Q99996-2

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

AN:

77778

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000597

Gnomad AMI

AF:

0.00186

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000622

Gnomad EAS

AF:

0.000804

Gnomad SAS

AF:

0.000770

Gnomad FIN

AF:

0.00539

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000815

Gnomad OTH

AF:

0.000921

GnomAD2 exomes

AF:

0.00678

AC:

565

AN:

83348

AF XY:

0.00652

show subpopulations

Gnomad AFR exome

AF:

0.00664

Gnomad AMR exome

AF:

0.0127

Gnomad ASJ exome

AF:

0.00500

Gnomad EAS exome

AF:

0.00305

Gnomad FIN exome

AF:

0.00471

Gnomad NFE exome

AF:

0.00514

Gnomad OTH exome

AF:

0.0128

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000930

AC:

906

AN:

974242

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

431

AN XY:

486270

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00273

AC:

AN:

20540

American (AMR)

AF:

0.0161

AC:

362

AN:

22476

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

17376

East Asian (EAS)

AF:

0.000227

AC:

AN:

30848

South Asian (SAS)

AF:

0.00244

AC:

115

AN:

47162

European-Finnish (FIN)

AF:

0.00164

AC:

AN:

35332

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

3206

European-Non Finnish (NFE)

AF:

0.000313

AC:

236

AN:

754940

Other (OTH)

AF:

0.00111

AC:

AN:

42362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.355

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000925

AC:

AN:

77830

Hom.:

Cov.:

AF XY:

0.000936

AC XY:

AN XY:

37390

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000596

AC:

AN:

18470

American (AMR)

AF:

0.00

AC:

AN:

8608

Ashkenazi Jewish (ASJ)

AF:

0.000622

AC:

AN:

1608

East Asian (EAS)

AF:

0.000804

AC:

AN:

2488

South Asian (SAS)

AF:

0.000772

AC:

AN:

2592

European-Finnish (FIN)

AF:

0.00539

AC:

AN:

4264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

140

European-Non Finnish (NFE)

AF:

0.000815

AC:

AN:

38024

Other (OTH)

AF:

0.000911

AC:

AN:

1098

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.305

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 04, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.6

(source)

DANN

Benign

0.49

PhyloP100

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00026

dbscSNV1_RF

Benign

0.0040

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over