19-532062-C-T

Variant names:

• chr19-532062-C-T
• rs778328367
• NM_004359.2:c.131C>T

Variant summary

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

The NM_004359.2(CDC34):​c.131C>T​(p.Ala44Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000219 in 1,369,654 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: 0.0000022 (0 hom.)
• Consequence: CDC34 NM_004359.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81

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.131C>T	p.Ala44Val	missense_variant	Exon 1 of 5	ENST00000215574.9	NP_004350.1
CDC34	XM_005259690.4	c.131C>T	p.Ala44Val	missense_variant	Exon 1 of 5		XP_005259747.1
CDC34	XM_006722952.3	c.131C>T	p.Ala44Val	missense_variant	Exon 1 of 5		XP_006723015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC34	ENST00000215574.9	c.131C>T	p.Ala44Val	missense_variant	Exon 1 of 5	1	NM_004359.2	ENSP00000215574.2
CDC34	ENST00000586283.6	c.29C>T	p.Ala10Val	missense_variant	Exon 1 of 5	3		ENSP00000475282.3
CDC34	ENST00000586788.1	n.294C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2
CDC34	ENST00000607527.5	c.-38C>T		upstream_gene_variant		5		ENSP00000476107.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1369654 Hom.: 0 Cov.: 30 AF XY: 0.00000294 AC XY: 2 AN XY: 679628

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: 0.00000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.131C>T (p.A44V) alteration is located in exon 1 (coding exon 1) of the CDC34 gene. This alteration results from a C to T substitution at nucleotide position 131, causing the alanine (A) at amino acid position 44 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	0.84
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.37	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.025	D
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.59
MutPred		0.44		Loss of catalytic residue at A44 (P = 0.2946);
MVP		0.37
MPC		2.0
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.69

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: rs778328367; hg19: chr19-532062; COSMIC: COSV105074737; COSMIC: COSV105074737;