chr7-92079584-A-G

Variant names:

• chr7-92079584-A-G
• rs35759833
• NM_005751.5:c.7451A>G

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.7451A>G​(p.Lys2484Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,678 control chromosomes in the GnomAD database, including 13,938 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (984 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12954 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.723
• Publications: 25 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=0.0012037754).
• BP6: Variant 7-92079584-A-G is Benign according to our data. Variant chr7-92079584-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 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.7451A>G	p.Lys2484Arg	missense	Exon 31 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.7427A>G	p.Lys2476Arg	missense	Exon 31 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.2096A>G	p.Lys699Arg	missense	Exon 10 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.7451A>G	p.Lys2484Arg	missense	Exon 31 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.2096A>G	p.Lys699Arg	missense	Exon 10 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000394534.7	TSL:1	c.944A>G	p.Lys315Arg	missense	Exon 4 of 23	ENSP00000378042.3	H7BYL6

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15253 AN: 152164 Hom.: 985 Cov.: 32

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.0796

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0281

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.0998

GnomAD2 exomes AF: 0.107 AC: 26831 AN: 249680 AF XY: 0.110

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.0589

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.0271

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.129 AC: 188791 AN: 1461396 Hom.: 12954 Cov.: 33 AF XY: 0.130 AC XY: 94146 AN XY: 726976

African (AFR) AF: 0.0258 AC: 865 AN: 33476

American (AMR) AF: 0.0617 AC: 2758 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3040 AN: 26126

East Asian (EAS) AF: 0.0168 AC: 667 AN: 39664

South Asian (SAS) AF: 0.104 AC: 8949 AN: 86230

European-Finnish (FIN) AF: 0.159 AC: 8448 AN: 53154

Middle Eastern (MID) AF: 0.154 AC: 887 AN: 5766

European-Non Finnish (NFE) AF: 0.140 AC: 155491 AN: 1111884

Other (OTH) AF: 0.127 AC: 7686 AN: 60380

GnomAD4 genome AF: 0.100 AC: 15249 AN: 152282 Hom.: 984 Cov.: 32 AF XY: 0.0994 AC XY: 7399 AN XY: 74454

African (AFR) AF: 0.0286 AC: 1191 AN: 41574

American (AMR) AF: 0.0794 AC: 1215 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3470

East Asian (EAS) AF: 0.0282 AC: 146 AN: 5186

South Asian (SAS) AF: 0.105 AC: 508 AN: 4824

European-Finnish (FIN) AF: 0.154 AC: 1627 AN: 10594

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9628 AN: 68014

Other (OTH) AF: 0.101 AC: 213 AN: 2116

Alfa AF: 0.123 Hom.: 3995

Bravo AF: 0.0901

TwinsUK AF: 0.140 AC: 519

ALSPAC AF: 0.135 AC: 520

ESP6500AA AF: 0.0304 AC: 134

ESP6500EA AF: 0.127 AC: 1095

ExAC AF: 0.108 AC: 13143

Asia WGS AF: 0.0930 AC: 323 AN: 3476

EpiCase AF: 0.139

EpiControl AF: 0.137

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 11 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0020
DANN	Benign	0.39
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.72
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.0070
Sift	Benign	0.55	T
Sift4G	Benign	0.40	T
Vest4		0.047
MPC		0.046
ClinPred		0.0014	T
GERP RS		-8.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.062
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: rs35759833; hg19: chr7-91708898; COSMIC: COSV107426297; COSMIC: COSV107426297;