7-40046007-A-T

Variant names:

• chr7-40046007-A-T
• NM_003718.5:c.2525A>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_003718.5(CDK13):​c.2525A>T​(p.Asn842Ile) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N842S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDK13 NM_003718.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-40046007-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK13	NM_003718.5	c.2525A>T	p.Asn842Ile	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.2525A>T	p.Asn842Ile	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder Uncertain:1

May 25, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.;T;.;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.2	D;D;.;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;.;.
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.94
MutPred		0.88		Loss of catalytic residue at N842 (P = 0.0571);Loss of catalytic residue at N842 (P = 0.0571);.;.;.;.;.;
MVP		0.94
MPC		2.8
ClinPred		1.0	D
GERP RS		4.6
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-40085606;