chr1-1703482-A-G

Position:

• chr1-1703482-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024011.4(CDK11A):​c.2054T>C​(p.Met685Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 16)
• Consequence: CDK11A NM_024011.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.18

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]

ACMG classification

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, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK11A	NM_024011.4	c.2054T>C	p.Met685Thr	missense_variant	18/20	ENST00000404249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK11A	ENST00000404249.8	c.2054T>C	p.Met685Thr	missense_variant	18/20	1	NM_024011.4	P1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2024

The c.2054T>C (p.M685T) alteration is located in exon 18 (coding exon 17) of the CDK11A gene. This alteration results from a T to C substitution at nucleotide position 2054, causing the methionine (M) at amino acid position 685 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.75
DEOGEN2	Benign	0.12	.;.;.;.;.;T
Eigen	Benign	0.097
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.7	.;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.014	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		0.81	.;.;P;.;P;.
Vest4		0.90
MutPred		0.81		.;.;Gain of catalytic residue at M685 (P = 0.0533);.;.;.;
MVP		0.60
MPC		0.22
ClinPred		0.84	D
GERP RS		2.5
Varity_R		0.46
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-1634921;