Genetic Variant AKAP13:p.Gly624Val (chr15-85579939-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007200.5(AKAP13):c.1871G>T(p.Gly624Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,613,956 control chromosomes in the GnomAD database, including 55,321 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 4148 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51173 hom. )

Consequence

AKAP13
NM_007200.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.250

Publications

35 publications found

Variant links:

Genes affected

AKAP13 (HGNC:371): (A-kinase anchoring protein 13) 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. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms containing c-terminal dbl oncogene homology (DH) and pleckstrin homology (PH) domains. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway, function as protein kinase A-anchoring proteins and, in addition, enhance ligand-dependent activity of estrogen receptors alpha and beta. [provided by RefSeq, Jul 2012]

AKAP13 links:

ENSG00000259375 (HGNC:):

ENSG00000259375 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003947228).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP13	NM_007200.5 link	c.1871G>T	p.Gly624Val	missense_variant	Exon 7 of 37	ENST00000394518.7	NP_009131.2	Q12802-1
AKAP13	NM_006738.6 link	c.1871G>T	p.Gly624Val	missense_variant	Exon 7 of 37		NP_006729.4	Q12802-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP13	ENST00000394518.7 link	c.1871G>T	p.Gly624Val	missense_variant	Exon 7 of 37	1	NM_007200.5	ENSP00000378026.3		Q12802-1

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

30878

AN:

152004

Hom.:

4152

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0479

Gnomad AMI

AF:

0.434

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.410

Gnomad EAS

AF:

0.0235

Gnomad SAS

AF:

0.175

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.405

Gnomad NFE

AF:

0.286

Gnomad OTH

AF:

0.250

GnomAD2 exomes

AF:

0.228

AC:

57291

AN:

250856

AF XY:

0.237

show subpopulations

Gnomad AFR exome

AF:

0.0419

Gnomad AMR exome

AF:

0.181

Gnomad ASJ exome

AF:

0.399

Gnomad EAS exome

AF:

0.0269

Gnomad FIN exome

AF:

0.234

Gnomad NFE exome

AF:

0.292

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.256

AC:

373697

AN:

1461834

Hom.:

51173

Cov.:

AF XY:

0.256

AC XY:

186140

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0434

AC:

1454

AN:

33480

American (AMR)

AF:

0.189

AC:

8444

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.398

AC:

10396

AN:

26136

East Asian (EAS)

AF:

0.0208

AC:

826

AN:

39700

South Asian (SAS)

AF:

0.202

AC:

17393

AN:

86256

European-Finnish (FIN)

AF:

0.236

AC:

12589

AN:

53396

Middle Eastern (MID)

AF:

0.377

AC:

2174

AN:

5768

European-Non Finnish (NFE)

AF:

0.275

AC:

305278

AN:

1111982

Other (OTH)

AF:

0.251

AC:

15143

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

18649

37297

55946

74594

93243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9746

19492

29238

38984

48730

<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:

0.203

AC:

30875

AN:

152122

Hom.:

4148

Cov.:

AF XY:

0.200

AC XY:

14875

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0478

AC:

1985

AN:

41520

American (AMR)

AF:

0.234

AC:

3583

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.410

AC:

1424

AN:

3470

East Asian (EAS)

AF:

0.0235

AC:

122

AN:

5182

South Asian (SAS)

AF:

0.175

AC:

843

AN:

4820

European-Finnish (FIN)

AF:

0.231

AC:

2443

AN:

10562

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.286

AC:

19440

AN:

67968

Other (OTH)

AF:

0.247

AC:

521

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1187

2374

3562

4749

5936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

322

644

966

1288

1610

<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:

0.273

Hom.:

18691

Bravo

AF:

0.195

TwinsUK

AF:

0.259

AC:

962

ALSPAC

AF:

0.270

AC:

1040

ESP6500AA

AF:

0.0481

AC:

212

ESP6500EA

AF:

0.284

AC:

2442

ExAC

AF:

0.228

AC:

27629

Asia WGS

AF:

0.102

AC:

354

AN:

3478

EpiCase

AF:

0.307

EpiControl

AF:

0.311

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

6.9

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.026

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.61

T;T;T

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.6

.;L;L

PhyloP100

0.25

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.049

Sift

Uncertain

0.014

D;D;D

Sift4G

Benign

0.15

T;D;D

Polyphen

0.0010

.;B;B

Vest4

0.12, 0.083

MPC

0.19

ClinPred

0.023

GERP RS

0.36

Varity_R

0.17

gMVP

0.24

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over