dbSNP rs1266756785: CDK11A:p.Arg247Gln (chr1-1709526-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024011.4(CDK11A):c.740G>A(p.Arg247Gln) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00017 ( 2 hom., cov: 5)

Exomes 𝑓: 0.00051 ( 26 hom. )

Failed GnomAD Quality Control

Consequence

CDK11A
NM_024011.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.13

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13541073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK11A	NM_024011.4 link	c.740G>A	p.Arg247Gln	missense_variant	Exon 7 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.740G>A	p.Arg247Gln	missense_variant	Exon 7 of 20	1	NM_024011.4	ENSP00000384442.3		Q9UQ88-2

Frequencies

GnomAD3 genomes

AF:

0.000170

AC:

AN:

35312

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000871

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000261

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000222

AC:

AN:

9026

AF XY:

0.000426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000611

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000513

AC:

135

AN:

263120

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

137842

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9014

American (AMR)

AF:

0.000365

AC:

AN:

10958

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8268

East Asian (EAS)

AF:

0.00

AC:

AN:

19464

South Asian (SAS)

AF:

0.00147

AC:

AN:

27944

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15390

Middle Eastern (MID)

AF:

0.0112

AC:

AN:

978

European-Non Finnish (NFE)

AF:

0.000378

AC:

AN:

155956

Other (OTH)

AF:

0.00132

AC:

AN:

15148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000170

AC:

AN:

35370

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

15880

show subpopulations

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

African (AFR)

AF:

0.0000866

AC:

AN:

11546

American (AMR)

AF:

0.00

AC:

AN:

2936

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

968

East Asian (EAS)

AF:

0.00

AC:

AN:

1040

South Asian (SAS)

AF:

0.00151

AC:

AN:

664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000261

AC:

AN:

15340

Other (OTH)

AF:

0.00

AC:

AN:

426

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.740G>A (p.R247Q) alteration is located in exon 7 (coding exon 6) of the CDK11A gene. This alteration results from a G to A substitution at nucleotide position 740, causing the arginine (R) at amino acid position 247 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.016

.;.;.;.;.;T

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.97

.;D;D;D;D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.14

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

.;.;.;.;M;M

PhyloP100

4.1

PROVEAN

Benign

-0.62

N;N;N;N;N;N

REVEL

Benign

0.071

Sift

Uncertain

0.013

D;D;D;D;D;D

Sift4G

Benign

0.31

T;T;T;T;T;T

Polyphen

1.0, 1.0, 1.0

.;.;D;D;D;.

Vest4

0.21

MutPred

0.20

.;.;.;Loss of methylation at R246 (P = 0.053);.;.;

MVP

0.19

MPC

0.82

ClinPred

0.29

GERP RS

2.7

Varity_R

0.11

gMVP

0.10

Mutation Taster

=86/14

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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rs1266756785

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over