17-47189169-T-C

Position:

• chr17-47189169-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001256.6(CDC27):​c.4A>G​(p.Thr2Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDC27 NM_001256.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.15

Genes affected

CDC27 (HGNC:1728): (cell division cycle 27) The protein encoded by this gene shares strong similarity with Saccharomyces cerevisiae protein Cdc27, and the gene product of Schizosaccharomyces pombe nuc 2. This protein is a component of the anaphase-promoting complex (APC), which is composed of eight protein subunits and is highly conserved in eukaryotic cells. This complex catalyzes the formation of cyclin B-ubiquitin conjugate, which is responsible for the ubiquitin-mediated proteolysis of B-type cyclins. The protein encoded by this gene and three other members of the APC complex contain tetratricopeptide (TPR) repeats, which are important for protein-protein interactions. This protein was shown to interact with mitotic checkpoint proteins including Mad2, p55CDC and BUBR1, and it may thus be involved in controlling the timing of mitosis. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 2, 22 and Y. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36450386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC27	NM_001256.6	c.4A>G	p.Thr2Ala	missense_variant	1/19	ENST00000066544.8	NP_001247.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC27	ENST00000066544.8	c.4A>G	p.Thr2Ala	missense_variant	1/19	1	NM_001256.6	ENSP00000066544	P5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Esophageal atresia;C0034194:Pyloric stenosis Uncertain:1

Uncertain significance, no assertion criteria provided

research

Clinical Genetics, Erasmus University Medical Center

May 22, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T;.;.;.
Eigen	Benign	0.039
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.0	L;L;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.12	N;N;N;.
REVEL	Benign	0.23
Sift	Benign	0.033	D;D;D;.
Sift4G	Benign	0.51	T;D;T;.
Polyphen		0.88	P;.;D;.
Vest4		0.35
MutPred		0.24		Loss of glycosylation at T2 (P = 0.0184);Loss of glycosylation at T2 (P = 0.0184);Loss of glycosylation at T2 (P = 0.0184);Loss of glycosylation at T2 (P = 0.0184);
MVP		0.83
MPC		1.8
ClinPred		0.73	D
GERP RS		3.7
Varity_R		0.14
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs62077280; hg19: chr17-45266535; COSMIC: COSV50365198; COSMIC: COSV50365198;