14-64468957-G-A

Position:

chr14-64468957-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004857.3(AKAP5):c.563G>A(p.Arg188Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,614,140 control chromosomes in the GnomAD database, including 406 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 189 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 217 hom. )

Consequence

AKAP5
NM_004857.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.130

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016661584).

BP6

Variant 14-64468957-G-A is Benign according to our data. Variant chr14-64468957-G-A is described in ClinVar as [Benign]. Clinvar id is 779687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP5	NM_004857.3 linkuse as main transcript	c.563G>A	p.Arg188Gln	missense_variant	2/2	ENST00000394718.4	NP_004848.3	P24588Q6PG46
ZBTB25	NM_001304508.1 linkuse as main transcript	c.174-19319C>T		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.563G>A	p.Arg188Gln	missense_variant	2/2	1	NM_004857.3	ENSP00000378207.3	P24588
ZBTB25	ENST00000555220.5 linkuse as main transcript	c.174-19319C>T		intron_variant		1		ENSP00000450718.1	G3V2K3
AKAP5	ENST00000320636.5 linkuse as main transcript	c.563G>A	p.Arg188Gln	missense_variant	1/1	6		ENSP00000315615.5	P24588
ZBTB25	ENST00000555424.1 linkuse as main transcript	c.256+18157C>T		intron_variant		5		ENSP00000451046.1	G3V351

Frequencies

GnomAD3 genomes

AF:

0.0287

AC:

4370

AN:

152146

Hom.:

189

Cov.:

show subpopulations

Gnomad AFR

AF:

0.100

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.0201

GnomAD3 exomes

AF:

0.00768

AC:

1931

AN:

251406

Hom.:

AF XY:

0.00544

AC XY:

739

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.00535

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.00315

AC:

4602

AN:

1461876

Hom.:

217

Cov.:

AF XY:

0.00270

AC XY:

1963

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.106

Gnomad4 AMR exome

AF:

0.00595

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000224

Gnomad4 OTH exome

AF:

0.00777

GnomAD4 genome

AF:

0.0287

AC:

4375

AN:

152264

Hom.:

189

Cov.:

AF XY:

0.0277

AC XY:

2059

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0999

Gnomad4 AMR

AF:

0.0100

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.00523

Hom.:

Bravo

AF:

0.0331

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0990

AC:

436

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00934

AC:

1134

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.0

DANN

Benign

0.49

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.55

.;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.2

N;N

PrimateAI

Benign

0.16

PROVEAN

Benign

0.20

N;N

REVEL

Benign

0.0090

Sift

Benign

0.63

T;T

Sift4G

Benign

0.66

T;T

Polyphen

0.0020

B;B

Vest4

0.030

MVP

0.32

MPC

0.23

ClinPred

0.0013

GERP RS

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.028

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