NM_004857.3:c.563G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R188W) has been classified as Uncertain significance.

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

Publications

6 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004857.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP5	NM_004857.3	MANE Select	c.563G>A	p.Arg188Gln	missense	Exon 2 of 2	NP_004848.3	P24588
	ZBTB25	NM_001304508.1		c.174-19319C>T		intron	N/A	NP_001291437.1	G3V2K3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AKAP5	ENST00000394718.4	TSL:1 MANE Select	c.563G>A	p.Arg188Gln	missense	Exon 2 of 2	ENSP00000378207.3	P24588
ZBTB25	ENST00000555220.5	TSL:1	c.174-19319C>T		intron	N/A	ENSP00000450718.1	G3V2K3
AKAP5	ENST00000320636.5	TSL:6	c.563G>A	p.Arg188Gln	missense	Exon 1 of 1	ENSP00000315615.5	P24588

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

GnomAD2 exomes

AF:

0.00768

AC:

1931

AN:

251406

AF XY:

0.00544

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 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

African (AFR)

AF:

0.106

AC:

3554

AN:

33478

American (AMR)

AF:

0.00595

AC:

266

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.000255

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000224

AC:

249

AN:

1112004

Other (OTH)

AF:

0.00777

AC:

469

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

259

517

776

1034

1293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0287

AC:

4375

AN:

152264

Hom.:

189

Cov.:

AF XY:

0.0277

AC XY:

2059

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0999

AC:

4147

AN:

41512

American (AMR)

AF:

0.0100

AC:

153

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68022

Other (OTH)

AF:

0.0199

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

207

414

622

829

1036

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0108

Hom.:

147

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.0

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.27

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.2

PhyloP100

0.13

PrimateAI

Benign

0.16

PROVEAN

Benign

0.20

REVEL

Benign

0.0090

Sift

Benign

0.63

Sift4G

Benign

0.66

Polyphen

0.0020

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over