Genetic Variant CDK11A:p.Leu399Ser (chr1-1707458-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_024011.4(CDK11A):c.1196T>C(p.Leu399Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00283 in 148,598 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 28)

Exomes 𝑓: 0.00019 ( 22 hom. )

Failed GnomAD Quality Control

Consequence

CDK11A
NM_024011.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.41

Publications

9 publications found

Variant links:

Genes affected

CDK11A (HGNC:1730): (cyclin dependent kinase 11A) This gene encodes a member of the serine/threonine protein kinase family. Members of this kinase family are known to be essential for eukaryotic cell cycle control. Due to a segmental duplication, this gene shares very high sequence identity with a neighboring gene. These two genes are frequently deleted or altered in neuroblastoma. The protein kinase encoded by this gene can be cleaved by caspases and may play a role in cell apoptosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

CDK11A links:

ENSG00000268575 (HGNC:):

ENSG00000268575 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005014986).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK11A	NM_024011.4 link	c.1196T>C	p.Leu399Ser	missense_variant	Exon 11 of 20	ENST00000404249.8	NP_076916.2	Q9UQ88-2Q4VBY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK11A	ENST00000404249.8 link	c.1196T>C	p.Leu399Ser	missense_variant	Exon 11 of 20	1	NM_024011.4	ENSP00000384442.3		Q9UQ88-2

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

420

AN:

148488

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00979

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000869

Gnomad ASJ

AF:

0.000583

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000214

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000193

Gnomad OTH

AF:

0.00299

GnomAD2 exomes

AF:

0.00348

AC:

849

AN:

244268

AF XY:

0.00328

show subpopulations

Gnomad AFR exome

AF:

0.0240

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.000801

Gnomad EAS exome

AF:

0.00426

Gnomad FIN exome

AF:

0.000233

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.00320

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000192

AC:

279

AN:

1455460

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

723980

show subpopulations

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

African (AFR)

AF:

0.00601

AC:

198

AN:

32930

American (AMR)

AF:

0.000382

AC:

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25986

East Asian (EAS)

AF:

0.000101

AC:

AN:

39590

South Asian (SAS)

AF:

0.000187

AC:

AN:

85764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.0000244

AC:

AN:

1107614

Other (OTH)

AF:

0.000267

AC:

AN:

60000

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.261

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00283

AC:

421

AN:

148598

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

193

AN XY:

72622

show subpopulations

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

African (AFR)

AF:

0.00978

AC:

386

AN:

39460

American (AMR)

AF:

0.000868

AC:

AN:

14982

Ashkenazi Jewish (ASJ)

AF:

0.000583

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.000214

AC:

AN:

4674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000193

AC:

AN:

67186

Other (OTH)

AF:

0.00296

AC:

AN:

2028

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.278

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00165

Hom.:

ExAC

AF:

0.00913

AC:

1102

EpiCase

AF:

0.00378

EpiControl

AF:

0.00305

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.18

DEOGEN2

Benign

0.018

.;.;.;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.26

.;T;T;T;T;T

MetaRNN

Benign

0.0050

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.0

.;.;.;.;.;N

PhyloP100

5.4

PROVEAN

Benign

2.4

N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

0.89

T;T;T;T;T;T

Polyphen

0.0

.;.;B;.;B;.

Vest4

0.33

MVP

0.12

MPC

0.27

ClinPred

0.0020

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.22

Mutation Taster

=99/1

polymorphism

(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