rs1057519632

Positions:

• chr7-39999467-G-A

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.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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDK13 NM_003718.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 9.94

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 (HGNC:):

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, 0.988
• PP5: Variant 7-39999467-G-A is Pathogenic according to our data. Variant chr7-39999467-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 375737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK13	NM_003718.5	c.2149G>A	p.Gly717Arg	missense_variant	4/14	ENST00000181839.10	NP_003709.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK13	ENST00000181839.10	c.2149G>A	p.Gly717Arg	missense_variant	4/14	1	NM_003718.5	ENSP00000181839.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458618 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder Pathogenic:9

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 02, 2018	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Mar 13, 2024	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). -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Nov 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000375737). The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.99). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	May 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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 -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CDK13: PS2, PM1, PM2, PS4:Moderate, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 09, 2022	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 375737). 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. This variant is not present in population databases (gnomAD no frequency). 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). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2023

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

Pathogenic, criteria provided, single submitter

research

Bicknell laboratory, University of Otago

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;.;T;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;.;.;.
PrimateAI	Pathogenic	0.94	D
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	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96

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

LitVar

Other links and lift over

dbSNP: rs1057519632; hg19: chr7-40039066;