rs192046591

Positions:

• chr7-92031506-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000356239.8(AKAP9):​c.4246-6A>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000611 in 1,601,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (0 hom.)
• Consequence: AKAP9 ENST00000356239.8 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001633
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.71

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 7-92031506-A-T is Benign according to our data. Variant chr7-92031506-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 527098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92031506-A-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP9	NM_005751.5	c.4246-6A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3	c.4246-6A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_671714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8	c.4246-6A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005751.5	ENSP00000348573	P4

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000335 AC: 84 AN: 250960 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135718

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000599

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000636 AC: 921 AN: 1449040 Hom.: 0 Cov.: 28 AF XY: 0.000629 AC XY: 454 AN XY: 721752

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000752

Gnomad4 NFE exome AF: 0.000786

Gnomad4 OTH exome AF: 0.000550

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74470

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000581 Hom.: 0

Bravo AF: 0.000472

Asia WGS AF: 0.000290 AC: 1 AN: 3460

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.048
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: rs192046591; hg19: chr7-91660820;