7-92102725-G-T

Position:

• chr7-92102725-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_005751.5(AKAP9):​c.11229G>T​(p.Met3743Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,614,106 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin Lovd.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 8.10

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]

AKAP9 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1405668).
• BP6: Variant 7-92102725-G-T is Benign according to our data. Variant chr7-92102725-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 360853.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}. Variant chr7-92102725-G-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP9	NM_005751.5	c.11229G>T	p.Met3743Ile	missense_variant	46/50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3	c.11205G>T	p.Met3735Ile	missense_variant	46/50		NP_671714.1
AKAP9	NM_001379277.1	c.5874G>T	p.Met1958Ile	missense_variant	25/29		NP_001366206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8	c.11229G>T	p.Met3743Ile	missense_variant	46/50	1	NM_005751.5	ENSP00000348573.3

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152132 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 251152 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135830

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000171 AC: 250 AN: 1461858 Hom.: 1 Cov.: 32 AF XY: 0.000195 AC XY: 142 AN XY: 727238

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152248 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74444

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000876 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 3743 of the AKAP9 protein (p.Met3743Ile). This variant is present in population databases (rs143306820, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26743238, 30276209). ClinVar contains an entry for this variant (Variation ID: 360853). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2022

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
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	.;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.2	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;.;D
REVEL	Benign	0.27
Sift	Uncertain	0.022	D;.;D
Sift4G	Uncertain	0.020	.;.;D
Vest4		0.57
MVP		0.61
MPC		0.066
ClinPred		0.12	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143306820; hg19: chr7-91732039; COSMIC: COSV62359264; COSMIC: COSV62359264;