dbSNP rs6753459: AKAP19:p.Thr56Ile (chr2-190200027-C-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_001042519.2(AKAP19):c.167C>T(p.Thr56Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,613,724 control chromosomes in the GnomAD database, including 58,824 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.31 ( 8427 hom., cov: 32)

Exomes 𝑓: 0.26 ( 50397 hom. )

Consequence

AKAP19
NM_001042519.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.44

Publications

39 publications found

Variant links:

Genes affected

AKAP19 (HGNC:28191): (chromosome 2 open reading frame 88) Predicted to enable protein kinase A regulatory subunit binding activity. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

AKAP19 links:

HIBCH (HGNC:4908): (3-hydroxyisobutyryl-CoA hydrolase) This gene encodes the enzyme responsible for hydrolysis of both HIBYL-CoA and beta-hydroxypropionyl-CoA. Mutations in this gene have been associated with 3-hyroxyisobutyryl-CoA hydrolase deficiency. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

HIBCH Gene-Disease associations (from GenCC):

3-hydroxyisobutyryl-CoA hydrolase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

HIBCH 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=2.3433566E-4).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP19	NM_001042519.2 link	c.167C>T	p.Thr56Ile	missense_variant	Exon 2 of 2	ENST00000340623.4	NP_001035984.1	Q9BSF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2orf88	ENST00000340623.4 link	c.167C>T	p.Thr56Ile	missense_variant	Exon 2 of 2	1	NM_001042519.2	ENSP00000345107.4		Q9BSF0

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

47061

AN:

151938

Hom.:

8393

Cov.:

show subpopulations

Gnomad AFR

AF:

0.467

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.282

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.466

Gnomad SAS

AF:

0.239

Gnomad FIN

AF:

0.132

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.247

Gnomad OTH

AF:

0.322

GnomAD2 exomes

AF:

0.264

AC:

65682

AN:

249168

AF XY:

0.260

show subpopulations

Gnomad AFR exome

AF:

0.479

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.225

Gnomad EAS exome

AF:

0.477

Gnomad FIN exome

AF:

0.138

Gnomad NFE exome

AF:

0.249

Gnomad OTH exome

AF:

0.254

GnomAD4 exome

AF:

0.255

AC:

373053

AN:

1461668

Hom.:

50397

Cov.:

AF XY:

0.254

AC XY:

185043

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.481

AC:

16099

AN:

33472

American (AMR)

AF:

0.225

AC:

10046

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

5853

AN:

26134

East Asian (EAS)

AF:

0.495

AC:

19637

AN:

39696

South Asian (SAS)

AF:

0.235

AC:

20263

AN:

86250

European-Finnish (FIN)

AF:

0.145

AC:

7765

AN:

53418

Middle Eastern (MID)

AF:

0.356

AC:

2050

AN:

5766

European-Non Finnish (NFE)

AF:

0.248

AC:

275379

AN:

1111834

Other (OTH)

AF:

0.264

AC:

15961

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

16291

32582

48872

65163

81454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9528

19056

28584

38112

47640

<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:

0.310

AC:

47148

AN:

152056

Hom.:

8427

Cov.:

AF XY:

0.305

AC XY:

22656

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.467

AC:

19366

AN:

41444

American (AMR)

AF:

0.281

AC:

4295

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

756

AN:

3470

East Asian (EAS)

AF:

0.467

AC:

2414

AN:

5168

South Asian (SAS)

AF:

0.241

AC:

1161

AN:

4826

European-Finnish (FIN)

AF:

0.132

AC:

1397

AN:

10596

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.247

AC:

16798

AN:

67972

Other (OTH)

AF:

0.325

AC:

687

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1559

3119

4678

6238

7797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.274

Hom.:

16467

Bravo

AF:

0.331

TwinsUK

AF:

0.246

AC:

914

ALSPAC

AF:

0.238

AC:

917

ESP6500AA

AF:

0.447

AC:

1769

ESP6500EA

AF:

0.237

AC:

1970

ExAC

AF:

0.270

AC:

32678

Asia WGS

AF:

0.349

AC:

1210

AN:

3478

EpiCase

AF:

0.256

EpiControl

AF:

0.257

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.0080

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.0027

T;T;T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.16

.;T;.;.;T

MetaRNN

Benign

0.00023

T;T;T;T;T

MetaSVM

Benign

-0.91

PhyloP100

-1.4

PROVEAN

Benign

-1.5

N;N;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.41

T;T;T;T;T

Sift4G

Benign

0.52

T;T;T;T;T

Polyphen

0.0

B;.;B;B;B

Vest4

0.038

MPC

0.016

ClinPred

0.0032

GERP RS

-3.0

Varity_R

0.044

gMVP

0.42

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