17-76005298-C-G

Position:

• chr17-76005298-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001258.4(CDK3):​c.793C>G​(p.Gln265Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDK3 NM_001258.4 missense, splice_region
• Scores: Splicing: ADA: 0.04813
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

Genes affected

CDK3 (HGNC:1772): (cyclin dependent kinase 3) This gene encodes a member of the cyclin-dependent protein kinase family. The protein promotes entry into S phase, in part by activating members of the E2F family of transcription factors. The protein also associates with cyclin C and phosphorylates the retinoblastoma 1 protein to promote exit from G0. [provided by RefSeq, Jul 2008]

TEN1-CDK3 (HGNC:44420): (TEN1-CDK3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring TEN1 telomerase capping complex subunit homolog (S. cerevisiae) and cyclin-dependent kinase 3 (CDK3) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Oct 2011]

EVPL (HGNC:3503): (envoplakin) This gene encodes a member of the plakin family of proteins that forms a component of desmosomes and the epidermal cornified envelope. This gene is located in the tylosis oesophageal cancer locus on chromosome 17q25, and its deletion is associated with both familial and sporadic forms of oesophageal squamous cell carcinoma. Patients suffering from the autoimmune mucocutaneous disorder, paraneoplastic pemphigus, develop antibodies against the encoded protein. [provided by RefSeq, Jul 2016]

TEN1-CDK3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14768392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK3	NM_001258.4	c.793C>G	p.Gln265Glu	missense_variant, splice_region_variant	8/8	ENST00000448471.3	NP_001249.1
TEN1-CDK3	NR_037709.1	n.2629C>G		splice_region_variant, non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK3	ENST00000448471.3	c.793C>G	p.Gln265Glu	missense_variant, splice_region_variant	8/8	5	NM_001258.4	ENSP00000400088.1
TEN1-CDK3	ENST00000649294.1	n.*934C>G		splice_region_variant, non_coding_transcript_exon_variant	11/11			ENSP00000497034.1
TEN1-CDK3	ENST00000649294.1	n.*934C>G		3_prime_UTR_variant	11/11			ENSP00000497034.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250816 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461238 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

The c.793C>G (p.Q265E) alteration is located in exon 8 (coding exon 7) of the CDK3 gene. This alteration results from a C to G substitution at nucleotide position 793, causing the glutamine (Q) at amino acid position 265 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.89	L;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.072
Sift	Benign	0.031	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.0050	B;B
Vest4		0.097
MutPred		0.43		Gain of phosphorylation at Y269 (P = 0.1152);Gain of phosphorylation at Y269 (P = 0.1152);
MVP		0.27
MPC		0.43
ClinPred		0.21	T
GERP RS		4.2
Varity_R		0.24
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.048
dbscSNV1_RF	Benign	0.15
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: rs1017850235; hg19: chr17-74001379;