7-92040822-G-A

Variant names:

• chr7-92040822-G-A
• rs2230768
• NM_005751.5:c.4841G>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.4841G>A​(p.Arg1614Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,748 control chromosomes in the GnomAD database, including 31 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1614W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0078 (15 hom., cov: 31)
  • Exomes 𝑓: 0.00070 (16 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.527
• Publications: 11 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=0.0024280548).
• BP6: Variant 7-92040822-G-A is Benign according to our data. Variant chr7-92040822-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136330.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 = 0.00778 (1182/151938) while in subpopulation AFR AF = 0.0272 (1127/41440). AF 95% confidence interval is 0.0259. There are 15 homozygotes in GnomAd4. There are 516 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	NM_005751.5	MANE Select	c.4841G>A	p.Arg1614Gln	missense	Exon 18 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.4841G>A	p.Arg1614Gln	missense	Exon 18 of 50	NP_671714.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.4841G>A	p.Arg1614Gln	missense	Exon 18 of 50	ENSP00000348573.3
	AKAP9	ENST00000359028.7	TSL:5	c.4841G>A	p.Arg1614Gln	missense	Exon 18 of 51	ENSP00000351922.4
	AKAP9	ENST00000681412.1		c.4841G>A	p.Arg1614Gln	missense	Exon 18 of 49	ENSP00000506486.1

Frequencies

GnomAD3 genomes AF: 0.00777 AC: 1180 AN: 151822 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00186 AC: 467 AN: 251238 AF XY: 0.00122

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000704 AC: 1029 AN: 1461810 Hom.: 16 Cov.: 34 AF XY: 0.000611 AC XY: 444 AN XY: 727200

African (AFR) AF: 0.0240 AC: 802 AN: 33476

American (AMR) AF: 0.00110 AC: 49 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111986

Other (OTH) AF: 0.00149 AC: 90 AN: 60390

GnomAD4 genome AF: 0.00778 AC: 1182 AN: 151938 Hom.: 15 Cov.: 31 AF XY: 0.00695 AC XY: 516 AN XY: 74256

African (AFR) AF: 0.0272 AC: 1127 AN: 41440

American (AMR) AF: 0.00216 AC: 33 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67968

Other (OTH) AF: 0.00570 AC: 12 AN: 2104

Alfa AF: 0.00306 Hom.: 13

Bravo AF: 0.00852

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Long QT syndrome 11 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.89	T
PhyloP100		0.53
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.021
Sift	Benign	0.61	T
Sift4G	Benign	0.62	T
Vest4		0.10
MVP		0.17
MPC		0.066
ClinPred		0.00040	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.051
Mutation Taster		=100/0	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: rs2230768; hg19: chr7-91670136;