17-57106452-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_003488.4(AKAP1):c.988A>G(p.Ser330Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0662 in 143,616 control chromosomes in the GnomAD database, including 425 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 (★★).

Frequency

Genomes: 𝑓 0.066 ( 425 hom., cov: 30)

Exomes 𝑓: 0.036 ( 2525 hom. )

Failed GnomAD Quality Control

Consequence

AKAP1
NM_003488.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.98

Publications

15 publications found

Variant links:

Genes affected

AKAP1 (HGNC:367): (A-kinase anchoring protein 1) 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 type I and type II regulatory subunits of PKA and anchors them to the mitochondrion. This protein is speculated to be involved in the cAMP-dependent signal transduction pathway and in directing RNA to a specific cellular compartment. [provided by RefSeq, Jul 2008]

AKAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0015726388).

BP6

Variant 17-57106452-A-G is Benign according to our data. Variant chr17-57106452-A-G is described in ClinVar as [Benign]. Clinvar id is 770798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP1	NM_003488.4 link	c.988A>G	p.Ser330Gly	missense_variant	Exon 2 of 11	ENST00000337714.8	NP_003479.1	Q92667-1A0A140VK05

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP1	ENST00000337714.8 link	c.988A>G	p.Ser330Gly	missense_variant	Exon 2 of 11	1	NM_003488.4	ENSP00000337736.3		Q92667-1

Frequencies

GnomAD3 genomes

AF:

0.0663

AC:

9509

AN:

143500

Hom.:

425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0224

Gnomad AMI

AF:

0.342

Gnomad AMR

AF:

0.0652

Gnomad ASJ

AF:

0.0483

Gnomad EAS

AF:

0.00628

Gnomad SAS

AF:

0.0423

Gnomad FIN

AF:

0.0812

Gnomad MID

AF:

0.0545

Gnomad NFE

AF:

0.0930

Gnomad OTH

AF:

0.0684

GnomAD2 exomes

AF:

0.0243

AC:

5610

AN:

230600

AF XY:

0.0227

show subpopulations

Gnomad AFR exome

AF:

0.0251

Gnomad AMR exome

AF:

0.0209

Gnomad ASJ exome

AF:

0.0107

Gnomad EAS exome

AF:

0.00296

Gnomad FIN exome

AF:

0.0335

Gnomad NFE exome

AF:

0.0305

Gnomad OTH exome

AF:

0.0312

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0357

AC:

45761

AN:

1282852

Hom.:

2525

Cov.:

AF XY:

0.0370

AC XY:

23669

AN XY:

640214

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0593

AC:

1796

AN:

30272

American (AMR)

AF:

0.0293

AC:

1248

AN:

42630

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

872

AN:

24752

East Asian (EAS)

AF:

0.0137

AC:

542

AN:

39538

South Asian (SAS)

AF:

0.0403

AC:

3259

AN:

80964

European-Finnish (FIN)

AF:

0.0882

AC:

4409

AN:

49990

Middle Eastern (MID)

AF:

0.0292

AC:

158

AN:

5406

European-Non Finnish (NFE)

AF:

0.0326

AC:

31086

AN:

954672

Other (OTH)

AF:

0.0438

AC:

2391

AN:

54628

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

2466

4932

7397

9863

12329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<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:

0.0662

AC:

9503

AN:

143616

Hom.:

425

Cov.:

AF XY:

0.0645

AC XY:

4511

AN XY:

69940

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0224

AC:

841

AN:

37540

American (AMR)

AF:

0.0651

AC:

945

AN:

14506

Ashkenazi Jewish (ASJ)

AF:

0.0483

AC:

164

AN:

3396

East Asian (EAS)

AF:

0.00629

AC:

AN:

5084

South Asian (SAS)

AF:

0.0415

AC:

189

AN:

4554

European-Finnish (FIN)

AF:

0.0812

AC:

814

AN:

10026

Middle Eastern (MID)

AF:

0.0514

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0930

AC:

6085

AN:

65408

Other (OTH)

AF:

0.0677

AC:

134

AN:

1980

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.395

Heterozygous variant carriers

343

685

1028

1370

1713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0763

Hom.:

164

TwinsUK

AF:

0.104

AC:

385

ALSPAC

AF:

0.103

AC:

397

ExAC

AF:

0.00475

AC:

569

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.037

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.058

T;T;T;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.52

.;.;T;.;.;T

MetaRNN

Benign

0.0016

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;N;N;N;N;N

PhyloP100

-2.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.42

N;.;.;.;N;N

REVEL

Benign

0.021

Sift

Benign

0.48

T;.;.;.;T;T

Sift4G

Benign

0.48

T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;.

Vest4

0.029

MPC

0.22

ClinPred

0.0010

GERP RS

-2.2

PromoterAI

0.0076

Neutral

(source)

Varity_R

0.059

gMVP

0.081

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over