NM_052988.5:c.24C>A

Variant names:

• chr16-89686734-C-A
• rs185587002
• NM_052988.5:c.24C>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_052988.5(CDK10):​c.24C>A​(p.Cys8*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,280 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDK10 NM_052988.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.28
• Publications: 0 publications found

Genes affected

CDK10 (HGNC:1770): (cyclin dependent kinase 10) The protein encoded by this gene belongs to the CDK subfamily of the Ser/Thr protein kinase family. The CDK subfamily members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and are known to be essential for cell cycle progression. This kinase has been shown to play a role in cellular proliferation and its function is limited to cell cycle G2-M phase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

LINC02166 (HGNC:53027): (long intergenic non-protein coding RNA 2166)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-89686734-C-A is Pathogenic according to our data. Variant chr16-89686734-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 992884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK10	NM_052988.5	c.24C>A	p.Cys8*	stop_gained	Exon 1 of 13	ENST00000353379.12	NP_443714.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK10	ENST00000353379.12	c.24C>A	p.Cys8*	stop_gained	Exon 1 of 13	1	NM_052988.5	ENSP00000338673.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458280 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725264

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

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110406

Other (OTH) AF: 0.00 AC: 0 AN: 60200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

-

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Al Kaissi syndrome Pathogenic:1

-

Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.059	N
PhyloP100		-1.3
Vest4		0.47
GERP RS		0.024
PromoterAI		-0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=47/153	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs185587002; hg19: chr16-89753142;