13-114242133-A-C

Variant names:

• chr13-114242133-A-C
• rs753778546
• NM_001078645.3:c.394A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001078645.3(CDC16):​c.394A>C​(p.Ile132Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,606,240 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I132V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CDC16 NM_001078645.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.76
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001078645.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC16	NM_001078645.3	MANE Select	c.394A>C	p.Ile132Leu	missense	Exon 6 of 18	NP_001072113.1	Q13042-1
	CDC16	NM_003903.5		c.394A>C	p.Ile132Leu	missense	Exon 6 of 19	NP_003894.3
	CDC16	NM_001318517.3		c.391A>C	p.Ile131Leu	missense	Exon 6 of 19	NP_001305446.1	Q13042-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC16	ENST00000356221.8	TSL:1 MANE Select	c.394A>C	p.Ile132Leu	missense	Exon 6 of 18	ENSP00000348554.3	Q13042-1
	CDC16	ENST00000252457.9	TSL:1	c.391A>C	p.Ile131Leu	missense	Exon 6 of 19	ENSP00000252457.5	Q13042-2
	CDC16	ENST00000375308.5	TSL:1	c.112A>C	p.Ile38Leu	missense	Exon 6 of 19	ENSP00000364457.1	Q13042-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454034 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723084

African (AFR) AF: 0.00 AC: 0 AN: 32910

American (AMR) AF: 0.00 AC: 0 AN: 42416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25718

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 84234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1109908

Other (OTH) AF: 0.00 AC: 0 AN: 60088

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.52	N
PhyloP100		8.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.19
Sift	Benign	0.14	T
Sift4G	Benign	0.23	T
Polyphen		0.30	B
Vest4		0.74
MutPred		0.66		Loss of methylation at K129 (P = 0.0585)
MVP		0.51
MPC		0.15
ClinPred		0.74	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.53
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs753778546; hg19: chr13-115007608;