rs1057519633

Variant names:

• chr7-39999458-G-C
• rs1057519633
• NM_003718.5:c.2140G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-39999458-G-C
• chr7-39999458-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_003718.5(CDK13):​c.2140G>C​(p.Gly714Arg) 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)
• Consequence: CDK13 NM_003718.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 10 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, 0.992
• PP5: Variant 7-39999458-G-C is Pathogenic according to our data. Variant chr7-39999458-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 375738.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK13	NM_003718.5	c.2140G>C	p.Gly714Arg	missense_variant	Exon 4 of 14	ENST00000181839.10	NP_003709.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK13	ENST00000181839.10	c.2140G>C	p.Gly714Arg	missense_variant	Exon 4 of 14	1	NM_003718.5	ENSP00000181839.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder Pathogenic:2

Feb 24, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDK13 c.2140G>C; p.Gly714Arg variant (rs1057519633, ClinVar Variation ID: 375738) is reported de novo in the literature in multiple individuals with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (Hamilton 2018, Sifrim 2016). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.968). In addition, the glycine at codon 714 is located in the ATP binding site of the protein kinase domain, which is predicted to affect kinase activity (Bostwick 2017). Based on available information, this variant is considered to be pathogenic. References: Bostwick BL et al. Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. Genome Med. 2017;9(1):73. PMID: 28807008. Hamilton MJ et al. Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability. J Med Genet. 2018;55(1):28-38. PMID: 29021403. Sifrim A et al. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet. 2016;48(9):1060-1065. PMID: 27479907. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T;.;T;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;.;.;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.5	D;D;.;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;.;.
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.94
MutPred		0.95		Gain of phosphorylation at T715 (P = 0.12);Gain of phosphorylation at T715 (P = 0.12);.;.;.;.;.;
MVP		0.97
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		0.98
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs1057519633; hg19: chr7-40039057;