19-541368-C-T

Variant names:

• chr19-541368-C-T
• rs917167001
• NM_004359.2:c.527C>T

Variant summary

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

The NM_004359.2(CDC34):​c.527C>T​(p.Ala176Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDC34 NM_004359.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

CDC34 (HGNC:1734): (cell division cycle 34, ubiqiutin conjugating enzyme) The protein encoded by this gene is a member of the ubiquitin-conjugating enzyme family. Ubiquitin-conjugating enzyme catalyzes the covalent attachment of ubiquitin to other proteins. This protein is a part of the large multiprotein complex, which is required for ubiquitin-mediated degradation of cell cycle G1 regulators, and for the initiation of DNA replication. [provided by RefSeq, Jul 2008]

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 rank	MANE	Protein	UniProt
CDC34	NM_004359.2	c.527C>T	p.Ala176Val	missense_variant	Exon 5 of 5	ENST00000215574.9	NP_004350.1
CDC34	XM_006722952.3	c.523C>T	p.Arg175Trp	missense_variant	Exon 5 of 5		XP_006723015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC34	ENST00000215574.9	c.527C>T	p.Ala176Val	missense_variant	Exon 5 of 5	1	NM_004359.2	ENSP00000215574.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448756 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720222

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.527C>T (p.A176V) alteration is located in exon 5 (coding exon 5) of the CDC34 gene. This alteration results from a C to T substitution at nucleotide position 527, causing the alanine (A) at amino acid position 176 to be replaced by a valine (V). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	-0.076	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.034	D;T
Polyphen		1.0	D;.
Vest4		0.73
MutPred		0.27		Loss of loop (P = 0.0986);.;
MVP		0.63
MPC		2.2
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.77
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs917167001; hg19: chr19-541368; COSMIC: COSV52742969; COSMIC: COSV52742969;