rs139770404

Variant names:

• chr7-92066465-C-T
• rs139770404
• NM_005751.5:c.6249C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_005751.5(AKAP9):​c.6249C>T​(p.Phe2083Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,612,522 control chromosomes in the GnomAD database, including 8 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 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (8 hom.)
• Consequence: AKAP9 NM_005751.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.520
• Publications: 4 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 7-92066465-C-T is Benign according to our data. Variant chr7-92066465-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215513.
• BP7: Synonymous conserved (PhyloP=0.52 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.6249C>T	p.Phe2083Phe	synonymous	Exon 26 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.6249C>T	p.Phe2083Phe	synonymous	Exon 26 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.894C>T	p.Phe298Phe	synonymous	Exon 5 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.6249C>T	p.Phe2083Phe	synonymous	Exon 26 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.894C>T	p.Phe298Phe	synonymous	Exon 5 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000359028.7	TSL:5	c.6345C>T	p.Phe2115Phe	synonymous	Exon 27 of 51	ENSP00000351922.4	A0A0A0MRF6

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00101 AC: 254 AN: 250808 AF XY: 0.00101

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00195 AC: 2848 AN: 1460470 Hom.: 8 Cov.: 31 AF XY: 0.00189 AC XY: 1371 AN XY: 726628

African (AFR) AF: 0.000538 AC: 18 AN: 33428

American (AMR) AF: 0.000738 AC: 33 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53402

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.00237 AC: 2629 AN: 1110918

Other (OTH) AF: 0.00245 AC: 148 AN: 60334

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.000996 AC XY: 74 AN XY: 74262

African (AFR) AF: 0.000555 AC: 23 AN: 41412

American (AMR) AF: 0.000393 AC: 6 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 68002

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00108

EpiCase AF: 0.00213

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	AKAP9-related disorder (1)
-	-	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
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.4
DANN	Benign	0.73
PhyloP100		0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139770404; hg19: chr7-91695779; COSMIC: COSV62347446; COSMIC: COSV62347446;