17-19936288-T-C

Position:

• chr17-19936288-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007202.4(AKAP10):​c.1465A>G​(p.Lys489Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKAP10 NM_007202.4 missense, splice_region
• Scores: Splicing: ADA: 0.1629
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

AKAP10 (HGNC:368): (A-kinase anchoring protein 10) This gene encodes a member of the A-kinase anchor protein family. A-kinase anchor proteins bind to the regulatory subunits of protein kinase A (PKA) and confine the holoenzyme to discrete locations within the cell. The encoded protein is localized to mitochondria and interacts with both the type I and type II regulatory subunits of PKA. Polymorphisms in this gene may be associated with increased risk of arrhythmias and sudden cardiac death. [provided by RefSeq, May 2012]

AKAP10 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3026896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP10	NM_007202.4	c.1465A>G	p.Lys489Glu	missense_variant, splice_region_variant	9/15	ENST00000225737.11	NP_009133.2
AKAP10	NM_001330152.2	c.1465A>G	p.Lys489Glu	missense_variant, splice_region_variant	9/14		NP_001317081.1
AKAP10	XR_007065258.1	n.1614A>G		splice_region_variant, non_coding_transcript_exon_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP10	ENST00000225737.11	c.1465A>G	p.Lys489Glu	missense_variant, splice_region_variant	9/15	1	NM_007202.4	ENSP00000225737.6
AKAP10	ENST00000395536.7	c.1465A>G	p.Lys489Glu	missense_variant, splice_region_variant	9/14	5		ENSP00000378907.3
AKAP10	ENST00000460046.2	n.*255A>G		non_coding_transcript_exon_variant	4/4	3		ENSP00000464294.1
AKAP10	ENST00000460046.2	n.*255A>G		3_prime_UTR_variant	4/4	3		ENSP00000464294.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jun 26, 2024

The c.1465A>G (p.K489E) alteration is located in exon 9 (coding exon 9) of the AKAP10 gene. This alteration results from a A to G substitution at nucleotide position 1465, causing the lysine (K) at amino acid position 489 to be replaced by a glutamic acid (E). 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	Benign	0.17
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T;.
Eigen	Benign	0.064
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.23	N;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.23
Sift	Uncertain	0.018	D;D
Sift4G	Benign	0.079	T;T
Polyphen		0.043	B;P
Vest4		0.56
MutPred		0.52		Loss of methylation at K489 (P = 0.0033);Loss of methylation at K489 (P = 0.0033);
MVP		0.34
MPC		0.45
ClinPred		0.81	D
GERP RS		5.2
Varity_R		0.41
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.080		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: rs915973147; hg19: chr17-19839601;