15-85543845-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007200.5(AKAP13):c.552G>T(p.Leu184Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: AKAP13 NM_007200.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.676

Genes affected

AKAP13 (HGNC:371): (A-kinase anchoring protein 13) 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. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms containing c-terminal dbl oncogene homology (DH) and pleckstrin homology (PH) domains. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway, function as protein kinase A-anchoring proteins and, in addition, enhance ligand-dependent activity of estrogen receptors alpha and beta. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21330479).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP13	NM_007200.5	c.552G>T	p.Leu184Phe	missense_variant	5/37	ENST00000394518.7
AKAP13	NM_006738.6	c.552G>T	p.Leu184Phe	missense_variant	5/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP13	ENST00000394518.7	c.552G>T	p.Leu184Phe	missense_variant	5/37	1	NM_007200.5	A2
AKAP13	ENST00000361243.6	c.552G>T	p.Leu184Phe	missense_variant	5/37	1		A2
AKAP13	ENST00000559362.5	c.552G>T	p.Leu184Phe	missense_variant	5/15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251340 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461840 Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 20 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.552G>T (p.L184F) alteration is located in exon 5 (coding exon 4) of the AKAP13 gene. This alteration results from a G to T substitution at nucleotide position 552, causing the leucine (L) at amino acid position 184 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	0.72	N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D;N;N
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.60, 0.63
MutPred		0.20		Loss of MoRF binding (P = 0.1312);Loss of MoRF binding (P = 0.1312);Loss of MoRF binding (P = 0.1312);
MVP		0.73
MPC		0.25
ClinPred		0.60	D
GERP RS		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs775361535; hg19: chr15-86087076; COSMIC: COSV63457448; COSMIC: COSV63457448;