14-64468777-C-T

Position:

chr14-64468777-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The ENST00000394718.4(AKAP5):c.383C>T(p.Pro128Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

AKAP5
ENST00000394718.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.81

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]

AKAP5 links:

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]

ZBTB25 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.781

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP5	NM_004857.3 linkuse as main transcript	c.383C>T	p.Pro128Leu	missense_variant	2/2	ENST00000394718.4	NP_004848.3
ZBTB25	NM_001304508.1 linkuse as main transcript	c.174-19139G>A		intron_variant			NP_001291437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
AKAP5	ENST00000394718.4 linkuse as main transcript	c.383C>T	p.Pro128Leu	missense_variant	2/2	1	NM_004857.3	ENSP00000378207	P1
ZBTB25	ENST00000555220.5 linkuse as main transcript	c.174-19139G>A		intron_variant		1		ENSP00000450718
AKAP5	ENST00000320636.5 linkuse as main transcript	c.383C>T	p.Pro128Leu	missense_variant	1/1			ENSP00000315615	P1
ZBTB25	ENST00000555424.1 linkuse as main transcript	c.256+18337G>A		intron_variant		5		ENSP00000451046

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250884

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727222

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:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2021

The c.383C>T (p.P128L) alteration is located in exon 2 (coding exon 1) of the AKAP5 gene. This alteration results from a C to T substitution at nucleotide position 383, causing the proline (P) at amino acid position 128 to be replaced by a leucine (L). 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

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;D

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.72

.;T

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-9.3

D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

D;D

Vest4

0.77

MutPred

0.47

Gain of catalytic residue at P128 (P = 0.0044);Gain of catalytic residue at P128 (P = 0.0044);

MVP

0.71

MPC

0.71

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over