7-92086348-C-T

Position:

• chr7-92086348-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000356239.8(AKAP9):​c.9145C>T​(p.Leu3049=) 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 ENST00000356239.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.03

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 136343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92086348-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP9	NM_005751.5	c.9145C>T	p.Leu3049=	synonymous_variant	37/50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3	c.9121C>T	p.Leu3041=	synonymous_variant	37/50		NP_671714.1
AKAP9	NM_001379277.1	c.3790C>T	p.Leu1264=	synonymous_variant	16/29		NP_001366206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8	c.9145C>T	p.Leu3049=	synonymous_variant	37/50	1	NM_005751.5	ENSP00000348573	P4

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

GnomAD3 exomes AF: 0.359 AC: 90129 AN: 251322 Hom.: 16961 AF XY: 0.365 AC XY: 49641 AN XY: 135826

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 SAS exome AF: 0.392

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

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.301

Gnomad4 ASJ exome AF: 0.541

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.389

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.388

Gnomad4 OTH exome AF: 0.375

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

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.543

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.387

Gnomad4 NFE AF: 0.386

Gnomad4 OTH AF: 0.368

Alfa AF: 0.383 Hom.: 14267

Bravo AF: 0.331

Asia WGS AF: 0.294 AC: 1026 AN: 3478

EpiCase AF: 0.391

EpiControl AF: 0.402

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 4626/13006=35% -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Long QT syndrome 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.9
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

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