NM_003718.5:c.2149G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_003718.5(CDK13):c.2149G>A(p.Gly717Arg) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G717V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDK13
NM_003718.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 9.94

Publications

13 publications found

Variant links:

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]

CDK13 Gene-Disease associations (from GenCC):

congenital heart defects, dysmorphic facial features, and intellectual developmental disorder
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

CDK13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_003718.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 7-39999467-G-A is Pathogenic according to our data. Variant chr7-39999467-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 375737.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
CDK13	NM_003718.5 link	c.2149G>A	p.Gly717Arg	missense_variant	Exon 4 of 14	ENST00000181839.10	NP_003709.3	Q14004-1A0A024RA85Q9BVE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK13	ENST00000181839.10 link	c.2149G>A	p.Gly717Arg	missense_variant	Exon 4 of 14	1	NM_003718.5	ENSP00000181839.4		Q14004-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725714

African (AFR)

AF:

0.00

AC:

AN:

33330

American (AMR)

AF:

0.00

AC:

AN:

44436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39492

South Asian (SAS)

AF:

0.00

AC:

AN:

85888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110156

Other (OTH)

AF:

0.00

AC:

AN:

60222

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder

Pathogenic:9

Jul 17, 2023

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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (MIM#617360). Dominant negative has also been suggested as a mechanism of disease, although not proven with functional studies (PMIDs: 29393965, 30904094, 32762766). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (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) 0600 - Variant is located in the annotated protein kinase domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed as de novo in over five individuals affected with CDK13-related conditions (DECIPHER). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 02, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 13, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The heterozygous p.Gly717Arg variant in CDK13 was identified by our study in one individual with Duane retraction syndrome; atrial septal defect; hypotonia; speech, language, and motor delays; and dysmorphic facial features, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Trio exome analysis showed this variant to be de novo. We believe this is a phenotype expansion for CDK13-related disorders. The variant has been previously reported in at least 11 unrelated individuals with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (PMID: 35043535, PMID: 33004838, PMID: 27479907, PMID: 29222009, PMID: 29021403, PMID: 28135719, ClinVar Accession SCV001190260.1, SCV001738366.1, SCV000803694.1, SCV002521011.1). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 10 individuals with confirmed paternity and maternity (PMID: 35043535, PMID: 33004838, PMID: 27479907, PMID: 29222009, PMID: 29021403, SCV000803694.1, SCV001738366.1, SCV001190260.1, PMID: 28135719). Multiple variants in the same region as the p.Gly717Arg variant have been reported in association with disease in the literature and in ClinVar, and the p.Gly717Arg variant is located in a region of CDK13 that is essential to its function as a protein kinase, suggesting that this variant is in a hot spot/functional domain and supports pathogenicity (PMID: 29021403; ClinVar ID: 375738, 977619, 449224). This variant has also been reported in ClinVar (Variation ID: 375737) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant congenital heart defects, dysmorphic facial features, and intellectual developmental disorder. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4, PM1, PM2_Supporting, PP3 (Richards 2015). -

Nov 23, 2017

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 29, 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 variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.73). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000375737 /PMID: 27479907 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27479907, 28135719, 29222009). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 27479907, 28135719, 29222009). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 26, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team -

May 22, 2019

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:4

Dec 21, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28135719, 29021403, 29222009, 27479907, 28867141, 30904094, 33004838, 31785789) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 717 of the CDK13 protein (p.Gly717Arg). 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: 27479907, 28135719, 29222009). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375737). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDK13 protein function. -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDK13: PS2, PM1, PM2, PS4:Moderate, PP2, PP3 -

Inborn genetic diseases

Pathogenic:1

Dec 04, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2149G>A (p.G717R) alteration is located in exon 4 (coding exon 4) of the CDK13 gene. This alteration results from a G to A substitution at nucleotide position 2149, causing the glycine (G) at amino acid position 717 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with CDK13-related neurodevelopmental disorder including global developmental delays/intellectual disability and dysmorphic features. Structural brain abnormalities and congenital heart defects have been noted in some individuals (Sifrim, 2016; Marwaha, 2022; Deciphering Developmental Disorders, 2017; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. The p.G717 amino acid is located in the protein kinase domain of CDK13 (Kohoutek, 2012), in particular in a highly conserved GEGTYG G-loop motif. This highly conserved motif regulates cyclin dependent kinase function in the following way: (1) the p.G712, p.G714, and p.G717 amino acid residues form a structural motif to ensure primary function; (2) the p.T715 and p.Y716 amino acid residues function as inhibitory sites; and (3) the p.Y716 residue interacts with the substrate backbone (Bártová, 2005). The p.G717 amino acid is essential in forming this G-loop, which functions in all protein kinases in nucleotide alignment, phosphorylation site regulatory function, formation of substrate binding box, and specificity for phosphorylation (Bártová, 2005). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Autism spectrum disorder

Pathogenic:1

Bicknell laboratory, University of Otago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;.;T;.;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

3.7

H;H;.;.;.;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-7.4

D;D;.;.;.;.;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;.;D;.;.

Polyphen

1.0

D;D;D;.;.;.;.

Vest4

0.95

MutPred

0.95

Loss of ubiquitination at K721 (P = 0.0418);Loss of ubiquitination at K721 (P = 0.0418);.;.;.;.;.;

MVP

0.95

MPC

2.7

ClinPred

1.0

GERP RS

5.5

PromoterAI

-0.060

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over