chr6-44396346-C-T

Variant summary

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

The NM_001253.4(CDC5L):​c.445C>T​(p.Leu149Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CDC5L
NM_001253.4 missense

Scores

5
6
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.33
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]

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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 Protein UniProt
CDC5LNM_001253.4 linkuse as main transcriptc.445C>T p.Leu149Phe missense_variant 5/16 ENST00000371477.4 NP_001244.1 Q99459
POLR1CNM_001318876.2 linkuse as main transcriptc.946-45544C>T 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.445C>T p.Leu149Phe missense_variant 5/161 NM_001253.4 ENSP00000360532.3 Q99459

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
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 GeneticsJul 26, 2021The c.445C>T (p.L149F) alteration is located in exon 5 (coding exon 5) of the CDC5L gene. This alteration results from a C to T substitution at nucleotide position 445, causing the leucine (L) at amino acid position 149 to be replaced by a phenylalanine (F). 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
0.97
BayesDel_addAF
Benign
-0.023
T
BayesDel_noAF
Benign
-0.27
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
D
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Benign
0.027
D
MetaRNN
Uncertain
0.49
T
MetaSVM
Benign
-0.54
T
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-3.4
D
REVEL
Benign
0.23
Sift
Benign
0.058
T
Sift4G
Benign
0.17
T
Polyphen
0.98
D
Vest4
0.51
MutPred
0.30
Loss of MoRF binding (P = 0.2542);
MVP
0.61
MPC
2.4
ClinPred
0.97
D
GERP RS
5.0
Varity_R
0.54
gMVP
0.45

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: chr6-44364083; API