6-44403855-A-T

Variant summary

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

The NM_001253.4(CDC5L):c.586A>T(p.Ile196Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDC5L NM_001253.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.08

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:):

ACMG classification

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	UniProt
CDC5L	NM_001253.4	c.586A>T	p.Ile196Leu	missense_variant	6/16	ENST00000371477.4
CDC5L	XM_047419605.1	c.151A>T	p.Ile51Leu	missense_variant	2/12
POLR1C	NM_001318876.2	c.946-38035A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC5L	ENST00000371477.4	c.586A>T	p.Ile196Leu	missense_variant	6/16	1	NM_001253.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460690 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726600

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 27, 2023

The c.586A>T (p.I196L) alteration is located in exon 6 (coding exon 6) of the CDC5L gene. This alteration results from a A to T substitution at nucleotide position 586, causing the isoleucine (I) at amino acid position 196 to be replaced by a leucine (L). 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	0.69
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.21
Sift	Benign	0.12	T
Sift4G	Benign	0.090	T
Polyphen		0.23	B
Vest4		0.71
MutPred		0.36		Loss of methylation at K200 (P = 0.0663);
MVP		0.61
MPC		0.58
ClinPred		0.82	D
GERP RS		6.0
Varity_R		0.56
gMVP		0.46

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: chr6-44371592;