14-64468442-G-C

Position:

chr14-64468442-G-C

Variant summary

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

The ENST00000394718.4(AKAP5):c.48G>C(p.Lys16Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,613,454 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 (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

AKAP5
ENST00000394718.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.13

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=0.10360706).

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP5	NM_004857.3 linkuse as main transcript	c.48G>C	p.Lys16Asn	missense_variant	2/2	ENST00000394718.4	NP_004848.3
ZBTB25	NM_001304508.1 linkuse as main transcript	c.174-18804C>G		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.48G>C	p.Lys16Asn	missense_variant	2/2	1	NM_004857.3	ENSP00000378207	P1
ZBTB25	ENST00000555220.5 linkuse as main transcript	c.174-18804C>G		intron_variant		1		ENSP00000450718
AKAP5	ENST00000320636.5 linkuse as main transcript	c.48G>C	p.Lys16Asn	missense_variant	1/1			ENSP00000315615	P1
ZBTB25	ENST00000555424.1 linkuse as main transcript	c.256+18672C>G		intron_variant		5		ENSP00000451046

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000191

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000152

AC:

AN:

250570

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135522

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000437

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

156

AN:

1461224

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

726916

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000897

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000751

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000151

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.000166

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

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

Mar 31, 2023

The c.48G>C (p.K16N) alteration is located in exon 2 (coding exon 1) of the AKAP5 gene. This alteration results from a G to C substitution at nucleotide position 48, causing the lysine (K) at amino acid position 16 to be replaced by an asparagine (N). 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

0.19

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Uncertain

0.59

D;D

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.47

.;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.078

Sift

Benign

0.064

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.87

P;P

Vest4

0.12

MutPred

0.19

Loss of ubiquitination at K16 (P = 3e-04);Loss of ubiquitination at K16 (P = 3e-04);

MVP

0.56

MPC

0.60

ClinPred

0.066

GERP RS

3.4

Varity_R

0.16

gMVP

0.095

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