rs73407505

Positions:

• chr7-92029945-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005751.5(AKAP9):​c.4199T>C​(p.Met1400Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00778 in 1,613,182 control chromosomes in the GnomAD database, including 544 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (264 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (280 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0260

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017569661).
• BP6: Variant 7-92029945-T-C is Benign according to our data. Variant chr7-92029945-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 191553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92029945-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.4199T>C	p.Met1400Thr	missense_variant	15/50	ENST00000356239.8
AKAP9	NM_147185.3	c.4199T>C	p.Met1400Thr	missense_variant	15/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.4199T>C	p.Met1400Thr	missense_variant	15/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5239 AN: 152132 Hom.: 263 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.0123 AC: 3083 AN: 251402 Hom.: 134 AF XY: 0.0104 AC XY: 1419 AN XY: 135874

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0239

Gnomad SAS exome AF: 0.0162

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00499 AC: 7293 AN: 1460932 Hom.: 280 Cov.: 30 AF XY: 0.00490 AC XY: 3559 AN XY: 726842

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.00597

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0221

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000212

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.0345 AC: 5252 AN: 152250 Hom.: 264 Cov.: 32 AF XY: 0.0344 AC XY: 2563 AN XY: 74464

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0249

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.00703 Hom.: 75

Bravo AF: 0.0383

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.108 AC: 474

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0146 AC: 1775

Asia WGS AF: 0.0320 AC: 113 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 03, 2019	Variant summary: AKAP9 c.4199T>C (p.Met1400Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.012 in 251402 control chromosomes in the gnomAD database, including 134 homozygotes. The observed variant frequency is well above the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4199T>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x benign, 1xlikely benign). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Long QT syndrome 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 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
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.9
DANN	Benign	0.30
DEOGEN2	Benign	0.25	.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.61	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.59	N;.;.;.
REVEL	Benign	0.0090
Sift	Benign	0.23	T;.;.;.
Sift4G	Benign	0.47	.;T;T;.
Vest4		0.12
MPC		0.059
ClinPred		0.00013	T
GERP RS		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.066

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: rs73407505; hg19: chr7-91659259;