rs1554333853

Variant names:

• chr7-40046006-A-G
• rs1554333853
• NM_003718.5:c.2524A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003718.5(CDK13):​c.2524A>G​(p.Asn842Asp) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N842S) has been classified 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:7 O:1
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 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, 6 uncertain in NM_003718.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-40046007-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 235887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 7-40046006-A-G is Pathogenic according to our data. Variant chr7-40046006-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 522794.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	c.2524A>G	p.Asn842Asp	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.2524A>G	p.Asn842Asp	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:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder Pathogenic:5 Other:1

Dec 08, 2016

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in PMID:28807008 (individual 1001). -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 27, 2022

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2016

Department of Medical Genetics, Oslo University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDK13 c.2524A>G; p.Asn842Asp variant (rs1554333853, ClinVar Variation ID: 522794) is reported in the literature in at least two individuals with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (Bostwick 2017, Hamilton 2018). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. The asparagine at codon 842 is located in the active site of the protein kinase domain (Bostwick 2017), which is predicted to abolish kinase activity. In one study, more than half (15/29) of the CDK13 variants identified altered the 842 codon, supporting the importance of this codon in proper protein function (Bostwick 2017). Furthermore, a different variant at this codon (p.Asn842Ser) is classified as pathogenic by several laboratories in ClinVar (Variation ID: 235887). Computational analyses predict that the p.Asn842Asp variant is deleterious (REVEL: 0.88). 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. -

Feb 15, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Apr 01, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine with aspartic acid at codon 842 of the CDK13 protein (p.Asn842Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with CDK13-related disease (PMID: 28807008, 29021403). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522794). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Asn842 amino acid residue in CDK13. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27479907, 28554332, 28807008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Apr 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28807008, 29021403, 29222009, 27479907) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;T;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H;.;.;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.6	D;D;.;.;.;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;.;.
Polyphen		1.0	D;P;D;.;.;.;.
Vest4		0.90
MutPred		0.91		Loss of MoRF binding (P = 0.0768);Loss of MoRF binding (P = 0.0768);.;.;.;.;.;
MVP		0.94
MPC		2.6
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		-0.0027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554333853; hg19: chr7-40085605;