6-44403874-G-C

Variant summary

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

The NM_001253.4(CDC5L):ā€‹c.605G>Cā€‹(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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

CDC5L
NM_001253.4 missense

Scores

4
9
6

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]
POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

Genome browser will be placed here

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 Protein UniProt
CDC5LNM_001253.4 linkuse as main transcriptc.605G>C p.Arg202Thr missense_variant 6/16 ENST00000371477.4 NP_001244.1 Q99459
CDC5LXM_047419605.1 linkuse as main transcriptc.170G>C p.Arg57Thr missense_variant 2/12 XP_047275561.1
POLR1CNM_001318876.2 linkuse as main transcriptc.946-38016G>C intron_variant NP_001305805.1 O15160-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDC5LENST00000371477.4 linkuse as main transcriptc.605G>C p.Arg202Thr missense_variant 6/161 NM_001253.4 ENSP00000360532.3 Q99459

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461038
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
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.:
32

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 submitterclinical testingAmbry GeneticsNov 03, 2022The 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
T
BayesDel_noAF
Benign
-0.15
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.37
T
Eigen
Uncertain
0.58
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.026
D
MetaRNN
Uncertain
0.57
D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-3.5
D
REVEL
Uncertain
0.31
Sift
Uncertain
0.018
D
Sift4G
Benign
0.11
T
Polyphen
0.82
P
Vest4
0.67
MutPred
0.30
Gain of phosphorylation at R202 (P = 0.0149);
MVP
0.60
MPC
0.82
ClinPred
0.97
D
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.

Other links and lift over

hg19: chr6-44371611; API