chr5-138189633-A-G

Position:

• chr5-138189633-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_004661.4(CDC23):​c.1623T>C​(p.Asp541Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,611,516 control chromosomes in the GnomAD database, including 81 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 0.012 (37 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (44 hom.)
• Consequence: CDC23 NM_004661.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.1726
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.37

Genes affected

CDC23 (HGNC:1724): (cell division cycle 23) The protein encoded by this gene shares strong similarity with Saccharomyces cerevisiae Cdc23, a protein essential for cell cycle progression through the G2/M transition. This protein is a component of anaphase-promoting complex (APC), which is composed of eight protein subunits and highly conserved in eukaryotic cells. APC catalyzes the formation of cyclin B-ubiquitin conjugate that is responsible for the ubiquitin-mediated proteolysis of B-type cyclins. This protein and 3 other members of the APC complex contain the TPR (tetratricopeptide repeat), a protein domain important for protein-protein interaction. [provided by RefSeq, Jul 2008]

CDC23 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 5-138189633-A-G is Benign according to our data. Variant chr5-138189633-A-G is described in ClinVar as [Benign]. Clinvar id is 783396.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1829/152256) while in subpopulation AFR AF= 0.0423 (1756/41540). AF 95% confidence interval is 0.0406. There are 37 homozygotes in gnomad4. There are 836 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1829 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC23	NM_004661.4	c.1623T>C	p.Asp541Asp	splice_region_variant, synonymous_variant	15/16	ENST00000394886.7	NP_004652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC23	ENST00000394886.7	c.1623T>C	p.Asp541Asp	splice_region_variant, synonymous_variant	15/16	1	NM_004661.4	ENSP00000378350.2
CDC23	ENST00000464806.1	n.400T>C		splice_region_variant, non_coding_transcript_exon_variant	2/3	2
CDC23	ENST00000475021.1	n.438T>C		splice_region_variant, non_coding_transcript_exon_variant	1/2	2
CDC23	ENST00000471692.1	n.*37T>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1827 AN: 152138 Hom.: 37 Cov.: 31

Gnomad AFR AF: 0.0423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00303 AC: 757 AN: 249802 Hom.: 17 AF XY: 0.00210 AC XY: 283 AN XY: 135004

Gnomad AFR exome AF: 0.0416

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00132 AC: 1933 AN: 1459260 Hom.: 44 Cov.: 31 AF XY: 0.00114 AC XY: 828 AN XY: 725638

Gnomad4 AFR exome AF: 0.0461

Gnomad4 AMR exome AF: 0.00149

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00294

GnomAD4 genome AF: 0.0120 AC: 1829 AN: 152256 Hom.: 37 Cov.: 31 AF XY: 0.0112 AC XY: 836 AN XY: 74458

Gnomad4 AFR AF: 0.0423

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00249 Hom.: 9

Bravo AF: 0.0135

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.17
dbscSNV1_RF	Benign	0.48
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

LitVar

Other links and lift over

dbSNP: rs2231480; hg19: chr5-137525322;