19-15355219-T-A

Variant names:

• chr19-15355219-T-A
• NM_005858.4:c.1775A>T

Variant summary

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

The NM_005858.4(AKAP8):​c.1775A>T​(p.Glu592Val) variant causes a missense 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKAP8 NM_005858.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.555
• Publications: 0 publications found

Genes affected

AKAP8 (HGNC:378): (A-kinase anchoring protein 8) This gene encodes a member of the A-kinase anchor protein family. A-kinase anchor proteins are scaffold proteins that contain a binding domain for the RI/RII subunit of protein kinase A (PKA) and recruit PKA and other signaling molecules to specific subcellular locations. This gene encodes a nuclear A-kinase anchor protein that binds to the RII alpha subunit of PKA and may play a role in chromosome condensation during mitosis by targeting PKA and the condensin complex to chromatin. A pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, May 2011]

LOC124904643 (HGNC:):

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=0.13190109).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP8	NM_005858.4	c.1775A>T	p.Glu592Val	missense_variant	Exon 14 of 14	ENST00000269701.7	NP_005849.1
LOC124904643	XR_007067146.1	n.286-6832T>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP8	ENST00000269701.7	c.1775A>T	p.Glu592Val	missense_variant	Exon 14 of 14	1	NM_005858.4	ENSP00000269701.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1775A>T (p.E592V) alteration is located in exon 14 (coding exon 14) of the AKAP8 gene. This alteration results from a A to T substitution at nucleotide position 1775, causing the glutamic acid (E) at amino acid position 592 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.56
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.064
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.037	D
Polyphen		0.73	P
Vest4		0.13
MutPred		0.16		Loss of solvent accessibility (P = 0.0199);
MVP		0.51
MPC		0.23
ClinPred		0.25	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.40
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: chr19-15466030;