rs146797353

Variant names:

• chr7-92017092-G-A
• rs146797353
• NM_005751.5:c.3827G>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.3827G>A​(p.Arg1276Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00766 in 1,570,710 control chromosomes in the GnomAD database, including 65 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1276R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0070 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (57 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.541
• Publications: 23 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=0.0028244555).
• BP6: Variant 7-92017092-G-A is Benign according to our data. Variant chr7-92017092-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00701 (1066/152140) while in subpopulation EAS AF = 0.0235 (122/5188). AF 95% confidence interval is 0.0201. There are 8 homozygotes in GnomAd4. There are 528 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.3827G>A	p.Arg1276Gln	missense	Exon 12 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.3827G>A	p.Arg1276Gln	missense	Exon 12 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.3827G>A	p.Arg1276Gln	missense	Exon 12 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000359028.7	TSL:5	c.3827G>A	p.Arg1276Gln	missense	Exon 12 of 51	ENSP00000351922.4	A0A0A0MRF6
	AKAP9	ENST00000681412.1		c.3827G>A	p.Arg1276Gln	missense	Exon 12 of 49	ENSP00000506486.1	A0A7P0TBH8

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1067 AN: 152022 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00636

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00701

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00930 AC: 2047 AN: 220076 AF XY: 0.0102

Gnomad AFR exome AF: 0.00420

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.0219

Gnomad FIN exome AF: 0.00118

Gnomad NFE exome AF: 0.00835

Gnomad OTH exome AF: 0.00663

GnomAD4 exome AF: 0.00773 AC: 10971 AN: 1418570 Hom.: 57 Cov.: 28 AF XY: 0.00816 AC XY: 5758 AN XY: 705376

African (AFR) AF: 0.00394 AC: 128 AN: 32488

American (AMR) AF: 0.00297 AC: 129 AN: 43442

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 513 AN: 25410

East Asian (EAS) AF: 0.0206 AC: 804 AN: 39036

South Asian (SAS) AF: 0.0164 AC: 1360 AN: 83116

European-Finnish (FIN) AF: 0.00148 AC: 77 AN: 52106

Middle Eastern (MID) AF: 0.00773 AC: 44 AN: 5690

European-Non Finnish (NFE) AF: 0.00681 AC: 7350 AN: 1078606

Other (OTH) AF: 0.00965 AC: 566 AN: 58676

GnomAD4 genome AF: 0.00701 AC: 1066 AN: 152140 Hom.: 8 Cov.: 32 AF XY: 0.00710 AC XY: 528 AN XY: 74376

African (AFR) AF: 0.00397 AC: 165 AN: 41552

American (AMR) AF: 0.00635 AC: 97 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3466

East Asian (EAS) AF: 0.0235 AC: 122 AN: 5188

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4830

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00701 AC: 476 AN: 67924

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00893 Hom.: 24

Bravo AF: 0.00706

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00886 AC: 76

ExAC AF: 0.00878 AC: 1059

Asia WGS AF: 0.0250 AC: 88 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	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	0.085
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.46
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.90	T
PhyloP100		0.54
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.014
Sift	Benign	0.60	T
Sift4G	Benign	0.94	T
Vest4		0.11
MVP		0.072
MPC		0.062
ClinPred		0.000025	T
GERP RS		-1.9
Varity_R		0.021
gMVP		0.057
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146797353; hg19: chr7-91646406;