Genetic Variant AKAP8:p.Ala575Gly (chr19-15355270-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005858.4(AKAP8):c.1724C>G(p.Ala575Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A575V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AKAP8
NM_005858.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.71

Publications

0 publications found

Variant links:

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]

AKAP8 links:

LOC124904643 (HGNC:):

LOC124904643 links:

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ACMG classification

Classification was made for transcript

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=0.07594454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP8	NM_005858.4 link	c.1724C>G	p.Ala575Gly	missense_variant	Exon 14 of 14	ENST00000269701.7	NP_005849.1	O43823
LOC124904643	XR_007067146.1 link	n.286-6781G>C		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP8	ENST00000269701.7 link	c.1724C>G	p.Ala575Gly	missense_variant	Exon 14 of 14	1	NM_005858.4	ENSP00000269701.1		O43823

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460730

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726746

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112004

Other (OTH)

AF:

0.0000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.71

M_CAP

Benign

0.0094

MetaRNN

Benign

0.076

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

1.7

PrimateAI

Benign

0.33

PROVEAN

Benign

0.080

REVEL

Benign

0.021

Sift

Benign

0.087

Sift4G

Benign

0.25

Polyphen

0.36

Vest4

0.15

MutPred

0.23

Loss of helix (P = 0.0068);

MVP

0.36

MPC

0.29

ClinPred

0.40

GERP RS

4.3

Varity_R

0.048

gMVP

0.083

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

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19-15355270-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over