NM_005751.5:c.5725G>A

Variant names:

• chr7-92061383-G-A
• rs200844952
• NM_005751.5:c.5725G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_005751.5(AKAP9):​c.5725G>A​(p.Ala1909Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,612,786 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000065 (1 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.30
• Publications: 9 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0121873915).
• BP6: Variant 7-92061383-G-A is Benign according to our data. Variant chr7-92061383-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360832.

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.5725G>A	p.Ala1909Thr	missense	Exon 23 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.5725G>A	p.Ala1909Thr	missense	Exon 23 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.370G>A	p.Ala124Thr	missense	Exon 2 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.5725G>A	p.Ala1909Thr	missense	Exon 23 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.370G>A	p.Ala124Thr	missense	Exon 2 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000359028.7	TSL:5	c.5821G>A	p.Ala1941Thr	missense	Exon 24 of 51	ENSP00000351922.4	A0A0A0MRF6

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151610 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00349

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000311 AC: 78 AN: 250844 AF XY: 0.000280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00413

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461062 Hom.: 1 Cov.: 31 AF XY: 0.0000578 AC XY: 42 AN XY: 726814

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.0000224 AC: 1 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00192 AC: 76 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111468

Other (OTH) AF: 0.0000994 AC: 6 AN: 60340

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151724 Hom.: 0 Cov.: 29 AF XY: 0.000175 AC XY: 13 AN XY: 74108

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00350 AC: 18 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10506

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000711 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.2	T
PhyloP100		7.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.28
Sift	Benign	0.082	T
Sift4G	Uncertain	0.053	T
Vest4		0.32
MVP		0.62
MPC		0.31
ClinPred		0.14	T
GERP RS		5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.18
gMVP		0.18
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200844952; hg19: chr7-91690697; COSMIC: COSV62353953;