rs780099038

Variant names:

• chr7-92086339-C-T
• rs780099038
• NM_005751.5:c.9136C>T
• AKAP9 p.Arg3046Trp

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005751.5(AKAP9):​c.9136C>T​(p.Arg3046Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. R3046Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.29
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21110114).

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.9136C>T	p.Arg3046Trp	missense	Exon 37 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.9112C>T	p.Arg3038Trp	missense	Exon 37 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.3781C>T	p.Arg1261Trp	missense	Exon 16 of 29	NP_001366206.1	A0A2R8Y590

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.9136C>T	p.Arg3046Trp	missense	Exon 37 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.3781C>T	p.Arg1261Trp	missense	Exon 16 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000394534.7	TSL:1	c.2629C>T	p.Arg877Trp	missense	Exon 10 of 23	ENSP00000378042.3	H7BYL6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251370 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461796 Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111940

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74248

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.0040
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.96	T
PhyloP100		2.3
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.098
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.024	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.12
Mutation Taster		=80/20	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs780099038;

hg19: chr7-91715653;

COSMIC: COSV62340743;