rs878853160

Variant names:

• chr7-40046007-A-G
• rs878853160
• NM_003718.5:c.2525A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-40046007-A-G
• chr7-40046007-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_003718.5(CDK13):​c.2525A>G​(p.Asn842Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDK13 NM_003718.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22 O:1
• Conservation: PhyloP100: 9.32

Genes affected

CDK13 (HGNC:1733): (cyclin dependent kinase 13) The protein encoded by this gene is a member of the cyclin-dependent serine/threonine protein kinase family. Members of this family are well known for their essential roles as master switches in cell cycle control. The exact function of this protein has not yet been determined, but it may play a role in mRNA processing and may be involved in regulation of hematopoiesis. Alternatively spliced transcript variants have been described.[provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain Protein kinase (size 293) in uniprot entity CDK13_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_003718.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 7-40046007-A-G is Pathogenic according to our data. Variant chr7-40046007-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-40046007-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK13	NM_003718.5	c.2525A>G	p.Asn842Ser	missense_variant	Exon 6 of 14	ENST00000181839.10	NP_003709.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK13	ENST00000181839.10	c.2525A>G	p.Asn842Ser	missense_variant	Exon 6 of 14	1	NM_003718.5	ENSP00000181839.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder Pathogenic:11 Other:1

Sep 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, haploinsufficiency, dominant negative and gain of function have been suggested in the literature (PMIDs: 30904094, 29393965, 28807008) (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in the protein kinase domain (PDB), where disease-associated missense variants are clustered (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been reported in many patients and shown to be de novo in multiple patients (ClinVar, Deciphering Developmental Disorders (DDD) Study). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 12, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDK13 c.2525A>G variant is classified as PATHOGENIC (PS4, PS2, PP3) The CDK13 c.2525A>G variant is a single nucleotide change in exon 6 of the CDK13 gene, which is predicted to change the amino acid asparagine at position 842 in the protein to serine. This recurrent variant has been identified in multiple individuals with global developmental delay or intellectual disability and dysmorphic features, with or without congenital heart defects, hypotonia or hearing loss (PMID:27479907, PMID:29021403, PMID:29222009) (PS4). A number of these cases have been shown to be de novo (PMID:28807008) (PS2). This variant is in dbSNP (rs878853160) but is absent from population databases (PM2). This variant has been reported in ClinVar as Pathogenic by multiple other diagnostic laboratories (Variation ID:235887), and has been reported as damaging for congenital heart disease, developmental delay and intellectual disability in HGMD (CM1610451). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Jun 10, 2020

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 03, 2020

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 15, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 12, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2020

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 22, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039581 /PMID: 23159249 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 25533962 /3billion dataset). The variant has been observed in at least two similarly affected unrelated individuals (3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). A different missense change at the same codon (p.Arg203Gln) has been reported to be associated with PACS1-related disorder (PMID: 28975623). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:8

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 842 of the CDK13 protein (p.Asn842Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CDK13-related conditions (PMID: 28807008). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 235887). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CDK13 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Sep 14, 2018

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28554332, 28867141, 29393965, 31883531, 27479907, 28807008, 29021403, 29222009, 28135719, 24999027, 19344873, 25560765, 28991257, 31238879, 31036916, 29738522, 32277047, 32368696, 32901917, 31785789) -

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Global developmental delay Pathogenic:1

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Marfanoid habitus and intellectual disability Pathogenic:1

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Inborn genetic diseases Pathogenic:1

Mar 15, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T;.;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.;.;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.6	D;D;.;.;.;.;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;.;.
Polyphen		1.0	D;P;D;.;.;.;.
Vest4		0.92
MutPred		0.90		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;.;.;.;.;
MVP		0.91
MPC		2.3
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853160; hg19: chr7-40085606;