chr7-39950703-A-G

Variant names:

• chr7-39950703-A-G
• rs1367392187
• NM_003718.5:c.62A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003718.5(CDK13):​c.62A>G​(p.Lys21Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,295,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CDK13 NM_003718.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45
• Publications: 5 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11255807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK13	NM_003718.5	c.62A>G	p.Lys21Arg	missense_variant	Exon 1 of 14	ENST00000181839.10	NP_003709.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK13	ENST00000181839.10	c.62A>G	p.Lys21Arg	missense_variant	Exon 1 of 14	1	NM_003718.5	ENSP00000181839.4
CDK13	ENST00000340829.10	c.62A>G	p.Lys21Arg	missense_variant	Exon 1 of 14	1		ENSP00000340557.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000332 AC: 2 AN: 60218 AF XY: 0.0000290

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1295982 Hom.: 0 Cov.: 33 AF XY: 0.00000157 AC XY: 1 AN XY: 637046

African (AFR) AF: 0.00 AC: 0 AN: 26004

American (AMR) AF: 0.0000916 AC: 2 AN: 21842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21620

East Asian (EAS) AF: 0.00 AC: 0 AN: 28324

South Asian (SAS) AF: 0.00 AC: 0 AN: 68398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3834

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1038348

Other (OTH) AF: 0.00 AC: 0 AN: 53678

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 21 of the CDK13 protein (p.Lys21Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CDK13-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CDK13 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.61	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		1.5
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.065
Sift	Benign	0.068	T;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.80	P;P
Vest4		0.085
MutPred		0.11		Loss of ubiquitination at K21 (P = 0.0326);Loss of ubiquitination at K21 (P = 0.0326);
MVP		0.30
MPC		1.5
ClinPred		0.26	T
GERP RS		3.7
PromoterAI		0.13	Neutral
Varity_R		0.13
gMVP		0.23
Mutation Taster		=96/4	polymorphism

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: rs1367392187; hg19: chr7-39990302;