rs73407505

Variant names:

• chr7-92029945-T-C
• rs73407505
• NM_005751.5:c.4199T>C

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.4199T>C​(p.Met1400Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00778 in 1,613,182 control chromosomes in the GnomAD database, including 544 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 0.034 (264 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (280 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0260
• Publications: 12 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=0.0017569661).
• BP6: Variant 7-92029945-T-C is Benign according to our data. Variant chr7-92029945-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 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.4199T>C	p.Met1400Thr	missense	Exon 15 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.4199T>C	p.Met1400Thr	missense	Exon 15 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.4199T>C	p.Met1400Thr	missense	Exon 15 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000359028.7	TSL:5	c.4199T>C	p.Met1400Thr	missense	Exon 15 of 51	ENSP00000351922.4	A0A0A0MRF6
	AKAP9	ENST00000681412.1		c.4199T>C	p.Met1400Thr	missense	Exon 15 of 49	ENSP00000506486.1	A0A7P0TBH8

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5239 AN: 152132 Hom.: 263 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.0123 AC: 3083 AN: 251402 AF XY: 0.0104

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0239

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00499 AC: 7293 AN: 1460932 Hom.: 280 Cov.: 30 AF XY: 0.00490 AC XY: 3559 AN XY: 726842

African (AFR) AF: 0.119 AC: 3963 AN: 33396

American (AMR) AF: 0.00597 AC: 267 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0221 AC: 875 AN: 39602

South Asian (SAS) AF: 0.0151 AC: 1305 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00488 AC: 28 AN: 5734

European-Non Finnish (NFE) AF: 0.000212 AC: 236 AN: 1111406

Other (OTH) AF: 0.0103 AC: 619 AN: 60334

GnomAD4 genome AF: 0.0345 AC: 5252 AN: 152250 Hom.: 264 Cov.: 32 AF XY: 0.0344 AC XY: 2563 AN XY: 74464

African (AFR) AF: 0.115 AC: 4767 AN: 41522

American (AMR) AF: 0.0136 AC: 208 AN: 15296

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

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5184

South Asian (SAS) AF: 0.0151 AC: 73 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68016

Other (OTH) AF: 0.0270 AC: 57 AN: 2114

Alfa AF: 0.0132 Hom.: 189

Bravo AF: 0.0383

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.108 AC: 474

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0146 AC: 1775

Asia WGS AF: 0.0320 AC: 113 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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	0.092
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.9
DANN	Benign	0.30
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.90	T
PhyloP100		0.026
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.0090
Sift	Benign	0.23	T
Sift4G	Benign	0.47	T
Vest4		0.12
MPC		0.059
ClinPred		0.00013	T
GERP RS		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.066
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs73407505; hg19: chr7-91659259;