chr14-64468908-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004857.3(AKAP5):​c.514C>A​(p.Gln172Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q172R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AKAP5
NM_004857.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.123
Variant links:
Genes affected
AKAP5 (HGNC:375): (A-kinase anchoring protein 5) 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. The encoded protein binds to the RII-beta regulatory subunit of PKA, and also to protein kinase C and the phosphatase calcineurin. It is predominantly expressed in cerebral cortex and may anchor the PKA protein at postsynaptic densities (PSD) and be involved in the regulation of postsynaptic events. It is also expressed in T lymphocytes and may function to inhibit interleukin-2 transcription by disrupting calcineurin-dependent dephosphorylation of NFAT. [provided by RefSeq, Jul 2008]
ZBTB25 (HGNC:13112): (zinc finger and BTB domain containing 25) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06188312).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AKAP5NM_004857.3 linkc.514C>A p.Gln172Lys missense_variant Exon 2 of 2 ENST00000394718.4 NP_004848.3 P24588Q6PG46
ZBTB25NM_001304508.1 linkc.174-19270G>T intron_variant Intron 2 of 2 NP_001291437.1 G3V2K3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AKAP5ENST00000394718.4 linkc.514C>A p.Gln172Lys missense_variant Exon 2 of 2 1 NM_004857.3 ENSP00000378207.3 P24588
ZBTB25ENST00000555220.5 linkc.174-19270G>T intron_variant Intron 2 of 2 1 ENSP00000450718.1 G3V2K3
AKAP5ENST00000320636.5 linkc.514C>A p.Gln172Lys missense_variant Exon 1 of 1 6 ENSP00000315615.5 P24588
ZBTB25ENST00000555424.1 linkc.256+18206G>T intron_variant Intron 2 of 2 5 ENSP00000451046.1 G3V351

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461846
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000122
Hom.:
0
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 01, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.514C>A (p.Q172K) alteration is located in exon 2 (coding exon 1) of the AKAP5 gene. This alteration results from a C to A substitution at nucleotide position 514, causing the glutamine (Q) at amino acid position 172 to be replaced by a lysine (K). 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
0.071
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
7.7
DANN
Benign
0.83
DEOGEN2
Benign
0.41
T;T
Eigen
Benign
-0.96
Eigen_PC
Benign
-0.98
FATHMM_MKL
Benign
0.070
N
LIST_S2
Benign
0.38
.;T
M_CAP
Benign
0.0045
T
MetaRNN
Benign
0.062
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Uncertain
2.1
M;M
PrimateAI
Benign
0.22
T
PROVEAN
Uncertain
-2.7
D;D
REVEL
Benign
0.11
Sift
Benign
0.39
T;T
Sift4G
Benign
0.89
T;T
Polyphen
0.0030
B;B
Vest4
0.074
MutPred
0.15
Gain of ubiquitination at Q172 (P = 0.0082);Gain of ubiquitination at Q172 (P = 0.0082);
MVP
0.54
MPC
0.26
ClinPred
0.058
T
GERP RS
0.71
Varity_R
0.13
gMVP
0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-64935626; API