chr7-92108527-T-G

Variant names:

• chr7-92108527-T-G
• rs756398963
• NM_005751.5:c.11580T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_005751.5(AKAP9):​c.11580T>G​(p.Gly3860Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: AKAP9 NM_005751.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.399
• Publications: 0 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-92108527-T-G is Benign according to our data. Variant chr7-92108527-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263701.
• BP7: Synonymous conserved (PhyloP=-0.399 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	NM_005751.5	MANE Select	c.11580T>G	p.Gly3860Gly	synonymous	Exon 49 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.11556T>G	p.Gly3852Gly	synonymous	Exon 49 of 50	NP_671714.1
	AKAP9	NM_001379277.1		c.6225T>G	p.Gly2075Gly	synonymous	Exon 28 of 29	NP_001366206.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.11580T>G	p.Gly3860Gly	synonymous	Exon 49 of 50	ENSP00000348573.3
	AKAP9	ENST00000491695.2	TSL:1	c.6225T>G	p.Gly2075Gly	synonymous	Exon 28 of 29	ENSP00000494626.2
	AKAP9	ENST00000394534.7	TSL:1	c.4572T>G	p.Gly1524Gly	synonymous	Exon 22 of 23	ENSP00000378042.3

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000223 AC: 56 AN: 251454 AF XY: 0.000250

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000999 AC: 146 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.0000976 AC XY: 71 AN XY: 727234

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000701 AC: 78 AN: 1112000

Other (OTH) AF: 0.000248 AC: 15 AN: 60396

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74352

African (AFR) AF: 0.0000482 AC: 2 AN: 41454

American (AMR) AF: 0.00164 AC: 25 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000317

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	AKAP9-related disorder (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
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.7
DANN	Benign	0.58
PhyloP100		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs756398963; hg19: chr7-91737841;