7-92086348-C-T

Variant names:

• chr7-92086348-C-T
• rs28927678
• NM_005751.5:c.9145C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005751.5(AKAP9):​c.9145C>T​(p.Leu3049Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,612,624 control chromosomes in the GnomAD database, including 116,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9216 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106861 hom.)
• Consequence: AKAP9 NM_005751.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.03
• Publications: 27 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 7-92086348-C-T is Benign according to our data. Variant chr7-92086348-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

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.9145C>T	p.Leu3049Leu	synonymous	Exon 37 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.9121C>T	p.Leu3041Leu	synonymous	Exon 37 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.3790C>T	p.Leu1264Leu	synonymous	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.9145C>T	p.Leu3049Leu	synonymous	Exon 37 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.3790C>T	p.Leu1264Leu	synonymous	Exon 16 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000394534.7	TSL:1	c.2638C>T	p.Leu880Leu	synonymous	Exon 10 of 23	ENSP00000378042.3	H7BYL6

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51516 AN: 151734 Hom.: 9219 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.359 AC: 90129 AN: 251322 AF XY: 0.365

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.171

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.382

GnomAD4 exome AF: 0.379 AC: 553345 AN: 1460774 Hom.: 106861 Cov.: 37 AF XY: 0.380 AC XY: 276170 AN XY: 726762

African (AFR) AF: 0.246 AC: 8225 AN: 33464

American (AMR) AF: 0.301 AC: 13464 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 14130 AN: 26126

East Asian (EAS) AF: 0.185 AC: 7328 AN: 39690

South Asian (SAS) AF: 0.389 AC: 33541 AN: 86234

European-Finnish (FIN) AF: 0.387 AC: 20655 AN: 53416

Middle Eastern (MID) AF: 0.417 AC: 2405 AN: 5764

European-Non Finnish (NFE) AF: 0.388 AC: 430985 AN: 1111016

Other (OTH) AF: 0.375 AC: 22612 AN: 60346

GnomAD4 genome AF: 0.339 AC: 51524 AN: 151850 Hom.: 9216 Cov.: 32 AF XY: 0.339 AC XY: 25164 AN XY: 74206

African (AFR) AF: 0.250 AC: 10360 AN: 41396

American (AMR) AF: 0.337 AC: 5149 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1882 AN: 3468

East Asian (EAS) AF: 0.174 AC: 896 AN: 5152

South Asian (SAS) AF: 0.386 AC: 1855 AN: 4802

European-Finnish (FIN) AF: 0.387 AC: 4072 AN: 10534

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26208 AN: 67910

Other (OTH) AF: 0.368 AC: 775 AN: 2106

Alfa AF: 0.373 Hom.: 19710

Bravo AF: 0.331

Asia WGS AF: 0.294 AC: 1026 AN: 3478

EpiCase AF: 0.391

EpiControl AF: 0.402

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Long QT syndrome 11 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.9
DANN	Benign	0.86
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs28927678; hg19: chr7-91715662; COSMIC: COSV62341369;