10-122833909-G-A

Variant summary

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

The NM_022034.6(CUZD1):c.1414C>T(p.Pro472Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CUZD1 NM_022034.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.973

Genes affected

CUZD1 (HGNC:17937): (CUB and zona pellucida like domains 1) Predicted to be involved in trypsinogen activation. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

FAM24B-CUZD1 (HGNC:):

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=0.34820747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUZD1	NM_022034.6	c.1414C>T	p.Pro472Ser	missense_variant	8/9	ENST00000392790.6
FAM24B-CUZD1	NR_037915.1	n.2090C>T		non_coding_transcript_exon_variant	10/11
CUZD1	NR_037912.2	n.1277C>T		non_coding_transcript_exon_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUZD1	ENST00000392790.6	c.1414C>T	p.Pro472Ser	missense_variant	8/9	1	NM_022034.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461282 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726924

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: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.1414C>T (p.P472S) alteration is located in exon 8 (coding exon 8) of the CUZD1 gene. This alteration results from a C to T substitution at nucleotide position 1414, causing the proline (P) at amino acid position 472 to be replaced by a serine (S). 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	Benign	0.14
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.98	D;D;D;D;D;D;D
PROVEAN	Benign	-0.73	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.28	T;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;D
Vest4		0.29
MutPred		0.50		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.79
MPC		0.39
ClinPred		0.85	D
GERP RS		4.4
Varity_R		0.066
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-124593425; COSMIC: COSV59027814;