rs6964587

Variant names:

• chr7-92001306-G-T
• rs6964587
• NM_005751.5:c.1389G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005751.5(AKAP9):​c.1389G>T​(p.Met463Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,613,566 control chromosomes in the GnomAD database, including 124,558 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M463V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.41 (13467 hom., cov: 32)
  • Exomes 𝑓: 0.39 (111091 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.232
• Publications: 99 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=4.2644082E-5).
• BP6: Variant 7-92001306-G-T is Benign according to our data. Variant chr7-92001306-G-T is described in ClinVar as Benign. ClinVar VariationId is 136347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

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.1389G>T	p.Met463Ile	missense	Exon 8 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.1389G>T	p.Met463Ile	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.1389G>T	p.Met463Ile	missense	Exon 8 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000359028.7	TSL:5	c.1389G>T	p.Met463Ile	missense	Exon 8 of 51	ENSP00000351922.4	A0A0A0MRF6
	AKAP9	ENST00000681412.1		c.1389G>T	p.Met463Ile	missense	Exon 8 of 49	ENSP00000506486.1	A0A7P0TBH8

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62827 AN: 151854 Hom.: 13449 Cov.: 32

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.424

GnomAD2 exomes AF: 0.378 AC: 94765 AN: 250610 AF XY: 0.380

Gnomad AFR exome AF: 0.512

Gnomad AMR exome AF: 0.311

Gnomad ASJ exome AF: 0.547

Gnomad EAS exome AF: 0.170

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.394

GnomAD4 exome AF: 0.387 AC: 564993 AN: 1461594 Hom.: 111091 Cov.: 46 AF XY: 0.387 AC XY: 281183 AN XY: 727114

African (AFR) AF: 0.513 AC: 17166 AN: 33474

American (AMR) AF: 0.316 AC: 14120 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 14177 AN: 26130

East Asian (EAS) AF: 0.184 AC: 7319 AN: 39686

South Asian (SAS) AF: 0.389 AC: 33559 AN: 86244

European-Finnish (FIN) AF: 0.387 AC: 20642 AN: 53374

Middle Eastern (MID) AF: 0.427 AC: 2464 AN: 5768

European-Non Finnish (NFE) AF: 0.388 AC: 431849 AN: 1111834

Other (OTH) AF: 0.392 AC: 23697 AN: 60382

GnomAD4 genome AF: 0.414 AC: 62896 AN: 151972 Hom.: 13467 Cov.: 32 AF XY: 0.411 AC XY: 30510 AN XY: 74264

African (AFR) AF: 0.510 AC: 21144 AN: 41444

American (AMR) AF: 0.361 AC: 5519 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1891 AN: 3468

East Asian (EAS) AF: 0.174 AC: 900 AN: 5182

South Asian (SAS) AF: 0.387 AC: 1865 AN: 4818

European-Finnish (FIN) AF: 0.387 AC: 4087 AN: 10572

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26272 AN: 67896

Other (OTH) AF: 0.423 AC: 890 AN: 2102

Alfa AF: 0.398 Hom.: 55101

Bravo AF: 0.416

TwinsUK AF: 0.378 AC: 1400

ALSPAC AF: 0.392 AC: 1510

ESP6500AA AF: 0.514 AC: 2261

ESP6500EA AF: 0.403 AC: 3466

ExAC AF: 0.382 AC: 46412

Asia WGS AF: 0.314 AC: 1095 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.403

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Long QT syndrome 11 (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Colorectal cancer (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.6
DANN	Benign	0.37
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.000043	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.23
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.036
Sift	Benign	0.064	T
Sift4G	Benign	0.067	T
Vest4		0.098
MPC		0.057
ClinPred		0.0019	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.075
Mutation Taster		=100/0	polymorphism (auto)

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: rs6964587; hg19: chr7-91630620; COSMIC: COSV62345589;