13-114243290-A-G

Variant summary

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

The NM_001078645.3(CDC16):c.575A>G(p.Lys192Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K192E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CDC16 NM_001078645.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

Genes affected

CDC16 (HGNC:1720): (cell division cycle 16) The protein encoded by this gene functions as a protein ubiquitin ligase and is a component of the multiprotein APC complex. The APC complex is a cyclin degradation system that governs exit from mitosis by targeting cell cycle proteins for degredation by the 26S proteasome. Each component protein of the APC complex is highly conserved among eukaryotic organisms. This protein, and other APC complex proteins, contain a tetratricopeptide repeat (TPR) domain; a protein domain that is often involved in protein-protein interactions and the assembly of multiprotein complexes. Multiple alternatively spliced transcript variants, encoding distinct proteins, have been identified. [provided by RefSeq, Jan 2016]

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
CDC16	NM_001078645.3	c.575A>G	p.Lys192Arg	missense_variant	7/18	ENST00000356221.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC16	ENST00000356221.8	c.575A>G	p.Lys192Arg	missense_variant	7/18	1	NM_001078645.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435994 Hom.: 0 Cov.: 25 AF XY: 0.00000140 AC XY: 1 AN XY: 716264

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: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

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 29, 2023

The c.575A>G (p.K192R) alteration is located in exon 7 (coding exon 7) of the CDC16 gene. This alteration results from a A to G substitution at nucleotide position 575, causing the lysine (K) at amino acid position 192 to be replaced by an arginine (R). 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	Benign	0.071
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T;.;.;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;.;.;D;D;.
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.83	N;.;N;N;N;N;N
REVEL	Benign	0.093
Sift	Benign	0.12	T;.;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;B;.;.
Vest4		0.24
MutPred		0.32		Loss of ubiquitination at K192 (P = 0.0148);.;Loss of ubiquitination at K192 (P = 0.0148);.;.;.;.;
MVP		0.28
MPC		0.068
ClinPred		0.39	T
GERP RS		5.8
Varity_R		0.14
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1236716733; hg19: chr13-115008765;