10-102423677-G-A

Variant names:

• chr10-102423677-G-A
• rs1050066028
• NM_024040.3:c.697C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024040.3(CUEDC2):​c.697C>T​(p.Arg233Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CUEDC2 NM_024040.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

Genes affected

CUEDC2 (HGNC:28352): (CUE domain containing 2) Predicted to enable ubiquitin binding activity. Acts upstream of or within negative regulation of cytokine production involved in inflammatory response and negative regulation of macrophage cytokine production. Located in cytosol; nuclear membrane; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUEDC2	NM_024040.3	c.697C>T	p.Arg233Trp	missense_variant	Exon 8 of 9	ENST00000369937.5	NP_076945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUEDC2	ENST00000369937.5	c.697C>T	p.Arg233Trp	missense_variant	Exon 8 of 9	1	NM_024040.3	ENSP00000358953.4
CUEDC2	ENST00000465409.1	n.548C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.697C>T (p.R233W) alteration is located in exon 8 (coding exon 7) of the CUEDC2 gene. This alteration results from a C to T substitution at nucleotide position 697, causing the arginine (R) at amino acid position 233 to be replaced by a tryptophan (W). 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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.61		Loss of disorder (P = 0.0053);
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.74
gMVP		0.73

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: rs1050066028; hg19: chr10-104183434;