7-40046006-A-G

Position:

• chr7-40046006-A-G

Variant summary

Our verdict is Pathogenic. Variant got 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:6 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 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 [Likely_pathogenic]. Clinvar id 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 [Likely_pathogenic]. Clinvar id is 522794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK13	NM_003718.5	c.2524A>G	p.Asn842Asp	missense_variant	6/14	ENST00000181839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK13	ENST00000181839.10	c.2524A>G	p.Asn842Asp	missense_variant	6/14	1	NM_003718.5	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Jan 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	May 18, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Dec 08, 2016	This variant has been reported in PMID:28807008 (individual 1001). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 01, 2020	For these reasons, this variant has been classified as Pathogenic. 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. 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 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). This variant is not present in population databases (ExAC no frequency). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2024	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;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0

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: rs1554333853; hg19: chr7-40085605;