7-91973723-C-G

Variant names:

• chr7-91973723-C-G
• rs1060503553
• NM_005751.5:c.61C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005751.5(AKAP9):​c.61C>G​(p.Arg21Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP9	NM_005751.5	c.61C>G	p.Arg21Gly	missense_variant	Exon 2 of 50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3	c.61C>G	p.Arg21Gly	missense_variant	Exon 2 of 50		NP_671714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8	c.61C>G	p.Arg21Gly	missense_variant	Exon 2 of 50	1	NM_005751.5	ENSP00000348573.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Apr 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.61C>G (p.R21G) alteration is located in exon 2 (coding exon 2) of the AKAP9 gene. This alteration results from a C to G substitution at nucleotide position 61, causing the arginine (R) at amino acid position 21 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	.;.;D;D;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.29	T
PhyloP100		2.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.1	D;.;D;.;.
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;.;D;.;.
Sift4G	Uncertain	0.021	.;D;D;D;.
Polyphen		1.0	.;.;D;.;.
Vest4		0.73
MutPred		0.33		Loss of helix (P = 0.0304);.;Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);.;
MVP		0.71
MPC		0.39
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.40
gMVP		0.20
Mutation Taster		=59/41	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: rs1060503553; hg19: chr7-91603037;