7-92102653-G-T

Variant names:

• chr7-92102653-G-T
• rs1060504955
• NM_005751.5:c.11157G>T

Variant summary

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

The NM_005751.5(AKAP9):​c.11157G>T​(p.Lys3719Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K3719K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.73
• 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]

CYP51A1 (HGNC:2649): (cytochrome P450 family 51 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein participates in the synthesis of cholesterol by catalyzing the removal of the 14alpha-methyl group from lanosterol. Homologous genes are found in all three eukaryotic phyla, fungi, plants, and animals, suggesting that this is one of the oldest cytochrome P450 genes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

CYP51A1 Gene-Disease associations (from GenCC):

• cataract

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

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.11157G>T	p.Lys3719Asn	missense_variant	Exon 46 of 50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3	c.11133G>T	p.Lys3711Asn	missense_variant	Exon 46 of 50		NP_671714.1
AKAP9	NM_001379277.1	c.5802G>T	p.Lys1934Asn	missense_variant	Exon 25 of 29		NP_001366206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8	c.11157G>T	p.Lys3719Asn	missense_variant	Exon 46 of 50	1	NM_005751.5	ENSP00000348573.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K3719N variant (also known as c.11157G>T), located in coding exon 46 of the AKAP9 gene, results from a G to T substitution at nucleotide position 11157. The lysine at codon 3719 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, 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	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	.;D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.83	T
PhyloP100		4.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.4	D;.;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	.;.;D
Vest4		0.83
MVP		0.54
MPC		0.37
ClinPred		1.0	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.62
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: 34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060504955; hg19: chr7-91731967; COSMIC: COSV104417035; COSMIC: COSV104417035;