rs60031334

Variant names:

• chr7-92001218-G-A
• rs60031334
• NM_005751.5:c.1301G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005751.5(AKAP9):​c.1301G>A​(p.Arg434Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00215 in 1,613,888 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R434W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (22 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.91
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029833019).
• BP6: Variant 7-92001218-G-A is Benign according to our data. Variant chr7-92001218-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1758/152164) while in subpopulation AFR AF = 0.0399 (1656/41524). AF 95% confidence interval is 0.0383. There are 35 homozygotes in GnomAd4. There are 860 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 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.1301G>A	p.Arg434Gln	missense	Exon 8 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.1301G>A	p.Arg434Gln	missense	Exon 8 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.1301G>A	p.Arg434Gln	missense	Exon 8 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000359028.7	TSL:5	c.1301G>A	p.Arg434Gln	missense	Exon 8 of 51	ENSP00000351922.4	A0A0A0MRF6
	AKAP9	ENST00000681412.1		c.1301G>A	p.Arg434Gln	missense	Exon 8 of 49	ENSP00000506486.1	A0A7P0TBH8

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1757 AN: 152046 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00284 AC: 711 AN: 250028 AF XY: 0.00230

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00117 AC: 1711 AN: 1461724 Hom.: 22 Cov.: 31 AF XY: 0.00101 AC XY: 734 AN XY: 727146

African (AFR) AF: 0.0406 AC: 1360 AN: 33468

American (AMR) AF: 0.00201 AC: 90 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1111964

Other (OTH) AF: 0.00278 AC: 168 AN: 60394

GnomAD4 genome AF: 0.0116 AC: 1758 AN: 152164 Hom.: 35 Cov.: 33 AF XY: 0.0116 AC XY: 860 AN XY: 74394

African (AFR) AF: 0.0399 AC: 1656 AN: 41524

American (AMR) AF: 0.00484 AC: 74 AN: 15278

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: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67962

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00448 Hom.: 16

Bravo AF: 0.0131

ESP6500AA AF: 0.0295 AC: 130

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00357 AC: 433

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.0063
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.9
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.091
Sift	Benign	0.47	T
Sift4G	Benign	0.21	T
Vest4		0.12
MVP		0.32
MPC		0.065
ClinPred		0.011	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.12
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs60031334; hg19: chr7-91630532;