6-44406319-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001253.4(CDC5L):c.759-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,595,978 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (8 hom., cov: 32)
  • Exomes 𝑓: 0.012 (123 hom.)
• Consequence: CDC5L NM_001253.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0005790
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-44406319-A-G is Benign according to our data. Variant chr6-44406319-A-G is described in ClinVar as [Benign]. Clinvar id is 2571251.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 1179 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC5L	NM_001253.4	c.759-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000371477.4
POLR1C	NM_001318876.2	c.946-35571A>G		intron_variant
CDC5L	XM_047419605.1	c.324-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC5L	ENST00000371477.4	c.759-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001253.4	P1

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1179 AN: 152210 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00832 AC: 2022 AN: 243082 Hom.: 16 AF XY: 0.00851 AC XY: 1117 AN XY: 131318

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00548

Gnomad EAS exome AF: 0.0000564

Gnomad SAS exome AF: 0.00341

Gnomad FIN exome AF: 0.00771

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.0116 AC: 16680 AN: 1443650 Hom.: 123 Cov.: 28 AF XY: 0.0113 AC XY: 8132 AN XY: 718522

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00312

Gnomad4 ASJ exome AF: 0.00648

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00319

Gnomad4 FIN exome AF: 0.00773

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00773 AC: 1178 AN: 152328 Hom.: 8 Cov.: 32 AF XY: 0.00728 AC XY: 542 AN XY: 74486

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00697

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0108 Hom.: 5

Bravo AF: 0.00732

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0128

EpiControl AF: 0.0135

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

CDC5L: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	9.9
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00058
dbscSNV1_RF	Benign	0.076
SpliceAI score (max)		0.020		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: rs79843509; hg19: chr6-44374056;