Variant 6-44403874-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001253.4(CDC5L):c.605G>C(p.Arg202Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,038 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R202K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDC5L
NM_001253.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.74

Variant links:

Genes affected

CDC5L (HGNC:1743): (cell division cycle 5 like) The protein encoded by this gene shares a significant similarity with Schizosaccharomyces pombe cdc5 gene product, which is a cell cycle regulator important for G2/M transition. This protein has been demonstrated to act as a positive regulator of cell cycle G2/M progression. It was also found to be an essential component of a non-snRNA spliceosome, which contains at least five additional protein factors and is required for the second catalytic step of pre-mRNA splicing. [provided by RefSeq, Jul 2008]

CDC5L links:

POLR1C (HGNC:):

POLR1C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDC5L	NM_001253.4 linkuse as main transcript	c.605G>C	p.Arg202Thr	missense_variant	6/16	ENST00000371477.4
CDC5L	XM_047419605.1 linkuse as main transcript	c.170G>C	p.Arg57Thr	missense_variant	2/12
POLR1C	NM_001318876.2 linkuse as main transcript	c.946-38016G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC5L	ENST00000371477.4 linkuse as main transcript	c.605G>C	p.Arg202Thr	missense_variant	6/16	1	NM_001253.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461038

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726762

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2022

The c.605G>C (p.R202T) alteration is located in exon 6 (coding exon 6) of the CDC5L gene. This alteration results from a G to C substitution at nucleotide position 605, causing the arginine (R) at amino acid position 202 to be replaced by a threonine (T). 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

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.58

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.31

Sift

Uncertain

0.018

Sift4G

Benign

0.11

Polyphen

0.82

Vest4

0.67

MutPred

0.30

Gain of phosphorylation at R202 (P = 0.0149);

MVP

0.60

MPC

0.82

ClinPred

0.97

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.58

gMVP

0.55

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over