chr17-19909228-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_007202.4(AKAP10):​c.1936A>G​(p.Ile646Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,612,096 control chromosomes in the GnomAD database, including 125,833 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.43 ( 14762 hom., cov: 33)
Exomes 𝑓: 0.39 ( 111071 hom. )

Consequence

AKAP10
NM_007202.4 missense

Scores

1
17

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided U:1B:1

Conservation

PhyloP100: 3.39

Publications

85 publications found
Variant links:
Genes affected
AKAP10 (HGNC:368): (A-kinase anchoring protein 10) This gene encodes a member of the A-kinase anchor protein family. A-kinase anchor proteins bind to the regulatory subunits of protein kinase A (PKA) and confine the holoenzyme to discrete locations within the cell. The encoded protein is localized to mitochondria and interacts with both the type I and type II regulatory subunits of PKA. Polymorphisms in this gene may be associated with increased risk of arrhythmias and sudden cardiac death. [provided by RefSeq, May 2012]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=5.4074975E-5).
BP6
Variant 17-19909228-T-C is Benign according to our data. Variant chr17-19909228-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5404.Status of the report is no_assertion_criteria_provided, 0 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AKAP10NM_007202.4 linkc.1936A>G p.Ile646Val missense_variant Exon 14 of 15 ENST00000225737.11 NP_009133.2 O43572A0A0S2Z4Z7
AKAP10NM_001330152.2 linkc.1762A>G p.Ile588Val missense_variant Exon 13 of 14 NP_001317081.1 E7EMD6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AKAP10ENST00000225737.11 linkc.1936A>G p.Ile646Val missense_variant Exon 14 of 15 1 NM_007202.4 ENSP00000225737.6 O43572
AKAP10ENST00000395536.7 linkc.1762A>G p.Ile588Val missense_variant Exon 13 of 14 5 ENSP00000378907.3 E7EMD6

Frequencies

GnomAD3 genomes
AF:
0.427
AC:
64970
AN:
151984
Hom.:
14728
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.583
Gnomad AMI
AF:
0.363
Gnomad AMR
AF:
0.431
Gnomad ASJ
AF:
0.370
Gnomad EAS
AF:
0.190
Gnomad SAS
AF:
0.288
Gnomad FIN
AF:
0.348
Gnomad MID
AF:
0.421
Gnomad NFE
AF:
0.377
Gnomad OTH
AF:
0.416
GnomAD2 exomes
AF:
0.371
AC:
93016
AN:
250460
AF XY:
0.364
show subpopulations
Gnomad AFR exome
AF:
0.590
Gnomad AMR exome
AF:
0.417
Gnomad ASJ exome
AF:
0.365
Gnomad EAS exome
AF:
0.182
Gnomad FIN exome
AF:
0.347
Gnomad NFE exome
AF:
0.382
Gnomad OTH exome
AF:
0.370
GnomAD4 exome
AF:
0.385
AC:
562722
AN:
1459994
Hom.:
111071
Cov.:
37
AF XY:
0.382
AC XY:
277236
AN XY:
726326
show subpopulations
African (AFR)
AF:
0.595
AC:
19869
AN:
33380
American (AMR)
AF:
0.419
AC:
18678
AN:
44544
Ashkenazi Jewish (ASJ)
AF:
0.368
AC:
9603
AN:
26102
East Asian (EAS)
AF:
0.202
AC:
7994
AN:
39646
South Asian (SAS)
AF:
0.303
AC:
26124
AN:
86086
European-Finnish (FIN)
AF:
0.346
AC:
18423
AN:
53224
Middle Eastern (MID)
AF:
0.407
AC:
2344
AN:
5760
European-Non Finnish (NFE)
AF:
0.393
AC:
436224
AN:
1110922
Other (OTH)
AF:
0.389
AC:
23463
AN:
60330
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
16215
32430
48646
64861
81076
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
13720
27440
41160
54880
68600
<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:
0.428
AC:
65059
AN:
152102
Hom.:
14762
Cov.:
33
AF XY:
0.424
AC XY:
31542
AN XY:
74368
show subpopulations
African (AFR)
AF:
0.584
AC:
24218
AN:
41482
American (AMR)
AF:
0.430
AC:
6572
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.370
AC:
1284
AN:
3472
East Asian (EAS)
AF:
0.190
AC:
982
AN:
5166
South Asian (SAS)
AF:
0.287
AC:
1388
AN:
4830
European-Finnish (FIN)
AF:
0.348
AC:
3685
AN:
10590
Middle Eastern (MID)
AF:
0.415
AC:
122
AN:
294
European-Non Finnish (NFE)
AF:
0.377
AC:
25602
AN:
67976
Other (OTH)
AF:
0.415
AC:
876
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
1898
3797
5695
7594
9492
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
584
1168
1752
2336
2920
<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:
0.396
Hom.:
47494
Bravo
AF:
0.444
TwinsUK
AF:
0.402
AC:
1490
ALSPAC
AF:
0.406
AC:
1564
ESP6500AA
AF:
0.581
AC:
2560
ESP6500EA
AF:
0.383
AC:
3298
ExAC
AF:
0.373
AC:
45349
Asia WGS
AF:
0.242
AC:
847
AN:
3478
EpiCase
AF:
0.386
EpiControl
AF:
0.374

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Reclassified - variant of unknown significance Uncertain:1
May 15, 2007
OMIM
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:literature only

- -

AKAP10-related disorder Benign:1
Oct 17, 2019
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.048
BayesDel_addAF
Benign
-0.64
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
16
DANN
Benign
0.49
DEOGEN2
Benign
0.062
T;.
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.34
FATHMM_MKL
Benign
0.070
N
LIST_S2
Benign
0.31
T;T
MetaRNN
Benign
0.000054
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-2.0
N;.
PhyloP100
3.4
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
0.31
N;N
REVEL
Benign
0.12
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
B;B
Vest4
0.12
MPC
0.18
ClinPred
0.0060
T
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.049
gMVP
0.19
Mutation Taster
=98/2
polymorphism (auto)

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

Other links and lift over

dbSNP: rs203462; hg19: chr17-19812541; COSMIC: COSV56731343; COSMIC: COSV56731343; API