chr7-92098173-A-G

Variant names:

• chr7-92098173-A-G
• rs144054367
• NM_005751.5:c.10672A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005751.5(AKAP9):​c.10672A>G​(p.Ile3558Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,612,382 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (2 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.11
• Publications: 10 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076205134).
• BP6: Variant 7-92098173-A-G is Benign according to our data. Variant chr7-92098173-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191527.
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	NM_005751.5	MANE Select	c.10672A>G	p.Ile3558Val	missense	Exon 43 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.10648A>G	p.Ile3550Val	missense	Exon 43 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.5317A>G	p.Ile1773Val	missense	Exon 22 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.10672A>G	p.Ile3558Val	missense	Exon 43 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.5317A>G	p.Ile1773Val	missense	Exon 22 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000394534.7	TSL:1	c.3664A>G	p.Ile1222Val	missense	Exon 16 of 23	ENSP00000378042.3	H7BYL6

Frequencies

GnomAD3 genomes AF: 0.000617 AC: 94 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000769 AC: 193 AN: 250846 AF XY: 0.000730

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000956

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000961

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000834 AC: 1217 AN: 1460028 Hom.: 2 Cov.: 29 AF XY: 0.000855 AC XY: 621 AN XY: 726478

African (AFR) AF: 0.000120 AC: 4 AN: 33446

American (AMR) AF: 0.000984 AC: 44 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53338

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.000923 AC: 1025 AN: 1110490

Other (OTH) AF: 0.00111 AC: 67 AN: 60318

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74498

African (AFR) AF: 0.000313 AC: 13 AN: 41584

American (AMR) AF: 0.00111 AC: 17 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000773 Hom.: 0

Bravo AF: 0.000752

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000725 AC: 88

EpiCase AF: 0.00120

EpiControl AF: 0.000949

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	AKAP9-related disorder (1)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.89	T
PhyloP100		1.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.045
Sift	Benign	0.042	D
Sift4G	Benign	0.20	T
Vest4		0.17
MVP		0.19
MPC		0.048
ClinPred		0.038	T
GERP RS		0.64
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.048
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144054367; hg19: chr7-91727487; COSMIC: COSV62352026; COSMIC: COSV62352026;