1-1636925-C-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_033486.3(CDK11B):c.1772G>T(p.Arg591Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CDK11B
NM_033486.3 missense
NM_033486.3 missense
Scores
8
2
2
Clinical Significance
Conservation
PhyloP100: 7.50
Genes affected
CDK11B (HGNC:1729): (cyclin dependent kinase 11B) 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, Apr 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.943
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDK11B | NM_033486.3 | c.1772G>T | p.Arg591Leu | missense_variant | 16/20 | ENST00000341832.11 | NP_277021.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDK11B | ENST00000341832.11 | c.1772G>T | p.Arg591Leu | missense_variant | 16/20 | 1 | NM_033486.3 | ENSP00000463048.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 31
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GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1453912Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 722248
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Data not reliable, filtered out with message: AC0;AS_VQSR
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74308
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Brachymorphism-onychodysplasia-dysphalangism syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Nov 25, 2024 | The heterozygous p.Arg591Leu variant in CDK11B was identified by our study, in the compound heterozygous state, in 2 siblings with Brachymorphism-onychodysplasia-dysphalangism syndrome. While this gene is still lacking sufficient evidence to establish a gene-disease relationship, we believe this is a possible novel gene candidate for Brachymorphism-onychodysplasia-dysphalangism syndrome. Given the limited information about this gene-disease relationship, the significance of the p.Arg591Leu variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in CDK11B we encourage you to reach out to us. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;.;T;.;T
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;D;.;.;.;.
Vest4
MVP
MPC
0.74
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at