rs147494754

Variant names:

• chr7-92065227-A-G
• rs147494754
• NM_005751.5:c.5978-4A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_005751.5(AKAP9):​c.5978-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,551,668 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (11 hom.)
• Consequence: AKAP9 NM_005751.5 splice_region, intron
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 2.63
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 7-92065227-A-G is Benign according to our data. Variant chr7-92065227-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220501.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

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.5978-4A>G		splice_region intron	N/A	NP_005742.4
	AKAP9	NM_147185.3		c.5978-4A>G		splice_region intron	N/A	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.623-4A>G		splice_region intron	N/A	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.5978-4A>G		splice_region intron	N/A	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.623-4A>G		splice_region intron	N/A	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000359028.7	TSL:5	c.6074-4A>G		splice_region intron	N/A	ENSP00000351922.4	A0A0A0MRF6

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00190 AC: 464 AN: 244260 AF XY: 0.00181

Gnomad AFR exome AF: 0.000648

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000747

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00343 AC: 4805 AN: 1399384 Hom.: 11 Cov.: 25 AF XY: 0.00324 AC XY: 2267 AN XY: 699860

African (AFR) AF: 0.000534 AC: 17 AN: 31850

American (AMR) AF: 0.0000678 AC: 3 AN: 44280

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25690

East Asian (EAS) AF: 0.00 AC: 0 AN: 38930

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83800

European-Finnish (FIN) AF: 0.000998 AC: 53 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5096

European-Non Finnish (NFE) AF: 0.00436 AC: 4612 AN: 1058582

Other (OTH) AF: 0.00203 AC: 118 AN: 58066

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74450

African (AFR) AF: 0.000673 AC: 28 AN: 41574

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00318 AC: 216 AN: 68022

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00264 Hom.: 1

Bravo AF: 0.00168

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Long QT syndrome 11 (2)
-	-	2	not provided (2)
-	-	1	AKAP9-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	23
DANN	Benign	0.59
PhyloP100		2.6
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.84		Position offset: 1

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

Other links and lift over

dbSNP: rs147494754; hg19: chr7-91694541;