NM_007200.5:c.4235C>T

Variant names:

• chr15-85639447-C-T
• NM_007200.5:c.4235C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007200.5(AKAP13):​c.4235C>T​(p.Pro1412Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKAP13 NM_007200.5 missense, splice_region
• Scores: Splicing: ADA: 0.5752
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12
• Publications: 0 publications found

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]

AKAP13-AS1 (HGNC:55975): (AKAP13 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21868247).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007200.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP13	NM_007200.5	MANE Select	c.4235C>T	p.Pro1412Leu	missense splice_region	Exon 9 of 37	NP_009131.2
	AKAP13	NM_006738.6		c.4235C>T	p.Pro1412Leu	missense splice_region	Exon 9 of 37	NP_006729.4
	AKAP13	NM_001270546.1		c.155C>T	p.Pro52Leu	missense splice_region	Exon 2 of 29	NP_001257475.1	B0AZU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP13	ENST00000394518.7	TSL:1 MANE Select	c.4235C>T	p.Pro1412Leu	missense splice_region	Exon 9 of 37	ENSP00000378026.3	Q12802-1
	AKAP13	ENST00000361243.6	TSL:1	c.4235C>T	p.Pro1412Leu	missense splice_region	Exon 9 of 37	ENSP00000354718.2	Q12802-2
	AKAP13	ENST00000560676.5	TSL:1	c.155C>T	p.Pro52Leu	missense splice_region	Exon 2 of 21	ENSP00000481485.1	A0A087WY36

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.018	D
Polyphen		0.96	D
Vest4		0.32
MutPred		0.19		Loss of helix (P = 0.028)
MVP		0.43
MPC		0.17
ClinPred		0.96	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.58
dbscSNV1_RF	Benign	0.34
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

Other links and lift over

hg19: chr15-86182678; COSMIC: COSV107461055;