dbSNP rs2061821: AKAP13:p.Met452Thr (chr15-85579423-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007200.5(AKAP13):c.1355T>C(p.Met452Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,613,822 control chromosomes in the GnomAD database, including 322,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.62 ( 28930 hom., cov: 32)

Exomes 𝑓: 0.63 ( 294008 hom. )

Consequence

AKAP13
NM_007200.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.08

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.007797E-6).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP13	NM_007200.5 link	c.1355T>C	p.Met452Thr	missense_variant	Exon 7 of 37	ENST00000394518.7	NP_009131.2	Q12802-1
AKAP13	NM_006738.6 link	c.1355T>C	p.Met452Thr	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.1355T>C	p.Met452Thr	missense_variant	Exon 7 of 37	1	NM_007200.5	ENSP00000378026.3		Q12802-1

Frequencies

GnomAD3 genomes

AF:

0.615

AC:

93428

AN:

151862

Hom.:

28912

Cov.:

show subpopulations

Gnomad AFR

AF:

0.591

Gnomad AMI

AF:

0.661

Gnomad AMR

AF:

0.610

Gnomad ASJ

AF:

0.723

Gnomad EAS

AF:

0.595

Gnomad SAS

AF:

0.557

Gnomad FIN

AF:

0.508

Gnomad MID

AF:

0.728

Gnomad NFE

AF:

0.646

Gnomad OTH

AF:

0.639

GnomAD3 exomes

AF:

0.607

AC:

152552

AN:

251302

Hom.:

46781

AF XY:

0.610

AC XY:

82864

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.583

Gnomad AMR exome

AF:

0.554

Gnomad ASJ exome

AF:

0.709

Gnomad EAS exome

AF:

0.581

Gnomad SAS exome

AF:

0.568

Gnomad FIN exome

AF:

0.511

Gnomad NFE exome

AF:

0.649

Gnomad OTH exome

AF:

0.631

GnomAD4 exome

AF:

0.633

AC:

924991

AN:

1461842

Hom.:

294008

Cov.:

AF XY:

0.632

AC XY:

459476

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.594

Gnomad4 AMR exome

AF:

0.565

Gnomad4 ASJ exome

AF:

0.711

Gnomad4 EAS exome

AF:

0.608

Gnomad4 SAS exome

AF:

0.568

Gnomad4 FIN exome

AF:

0.516

Gnomad4 NFE exome

AF:

0.646

Gnomad4 OTH exome

AF:

0.629

GnomAD4 genome

AF:

0.615

AC:

93492

AN:

151980

Hom.:

28930

Cov.:

AF XY:

0.608

AC XY:

45131

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.591

Gnomad4 AMR

AF:

0.610

Gnomad4 ASJ

AF:

0.723

Gnomad4 EAS

AF:

0.595

Gnomad4 SAS

AF:

0.556

Gnomad4 FIN

AF:

0.508

Gnomad4 NFE

AF:

0.646

Gnomad4 OTH

AF:

0.636

Alfa

AF:

0.648

Hom.:

77491

Bravo

AF:

0.620

TwinsUK

AF:

0.649

AC:

2406

ALSPAC

AF:

0.630

AC:

2428

ESP6500AA

AF:

0.594

AC:

2614

ESP6500EA

AF:

0.644

AC:

5540

ExAC

AF:

0.610

AC:

74115

Asia WGS

AF:

0.562

AC:

1955

AN:

3478

EpiCase

AF:

0.659

EpiControl

AF:

0.660

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

6.5

DANN

Benign

0.75

DEOGEN2

Benign

0.012

T;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.47

T;T;T

MetaRNN

Benign

0.0000050

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.90

.;L;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.76

N;N;N

REVEL

Benign

0.078

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0020, 0.0030

.;B;B

Vest4

0.024, 0.0090

MPC

0.041

ClinPred

0.0091

GERP RS

-8.7

Varity_R

0.033

gMVP

0.14

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over