NM_003718.5:c.18C>A

Variant names:

• chr7-39950659-C-A
• NM_003718.5:c.18C>A

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.18C>A​(p.Asp6Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000838 in 1,193,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: CDK13 NM_003718.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44
• Publications: 0 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=0.074721456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK13	NM_003718.5	c.18C>A	p.Asp6Glu	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.18C>A	p.Asp6Glu	missense_variant	Exon 1 of 14	1	NM_003718.5	ENSP00000181839.4
CDK13	ENST00000340829.10	c.18C>A	p.Asp6Glu	missense_variant	Exon 1 of 14	1		ENSP00000340557.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.38e-7 AC: 1 AN: 1193302 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 577492

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23812

American (AMR) AF: 0.00 AC: 0 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16880

East Asian (EAS) AF: 0.00 AC: 0 AN: 27038

South Asian (SAS) AF: 0.00 AC: 0 AN: 50348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3344

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 983438

Other (OTH) AF: 0.00 AC: 0 AN: 48778

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDK13 protein function. This variant has not been reported in the literature in individuals affected with CDK13-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 6 of the CDK13 protein (p.Asp6Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-0.99	T
PhyloP100		1.4
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.055
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.85	T;T
Polyphen		0.0	B;B
Vest4		0.052
MutPred		0.084		Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);
MVP		0.27
MPC		1.6
ClinPred		0.67	D
GERP RS		2.8
PromoterAI		0.15	Neutral
Varity_R		0.17
gMVP		0.16
Mutation Taster		=95/5	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

hg19: chr7-39990258;