14-64468561-C-T

Position:

chr14-64468561-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004857.3(AKAP5):c.167C>T(p.Ala56Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

AKAP5
NM_004857.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.203

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08439389).

BS2

High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP5	NM_004857.3 linkuse as main transcript	c.167C>T	p.Ala56Val	missense_variant	2/2	ENST00000394718.4	NP_004848.3	P24588Q6PG46
ZBTB25	NM_001304508.1 linkuse as main transcript	c.174-18923G>A		intron_variant			NP_001291437.1	G3V2K3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AKAP5	ENST00000394718.4 linkuse as main transcript	c.167C>T	p.Ala56Val	missense_variant	2/2	1	NM_004857.3	ENSP00000378207.3	P24588
ZBTB25	ENST00000555220.5 linkuse as main transcript	c.174-18923G>A		intron_variant		1		ENSP00000450718.1	G3V2K3
AKAP5	ENST00000320636.5 linkuse as main transcript	c.167C>T	p.Ala56Val	missense_variant	1/1	6		ENSP00000315615.5	P24588
ZBTB25	ENST00000555424.1 linkuse as main transcript	c.256+18553G>A		intron_variant		5		ENSP00000451046.1	G3V351

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250914

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

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:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000189

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000892

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

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

Aug 09, 2021

The c.167C>T (p.A56V) 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 167, causing the alanine (A) at amino acid position 56 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

-0.35

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

D;D

Eigen

Benign

-0.051

Eigen_PC

Benign

-0.096

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.47

.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.084

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.052

Sift

Benign

0.11

T;T

Sift4G

Benign

0.067

T;T

Polyphen

0.89

P;P

Vest4

0.056

MutPred

0.23

Gain of catalytic residue at G52 (P = 0.0011);Gain of catalytic residue at G52 (P = 0.0011);

MVP

0.44

MPC

0.21

ClinPred

0.44

GERP RS

3.6

Varity_R

0.099

gMVP

0.21

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