rs959019903

Variant names:

• chr10-122836335-G-A
• rs959019903
• NM_022034.6:c.833C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022034.6(CUZD1):​c.833C>T​(p.Ser278Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000782 in 1,522,212 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (1 hom.)
• Consequence: CUZD1 NM_022034.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.622
• Publications: 0 publications found

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]

CUZD1 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000286088 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022034.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUZD1	NM_022034.6	MANE Select	c.833C>T	p.Ser278Phe	missense	Exon 6 of 9	NP_071317.2
	CUZD1	NR_037912.2		n.696C>T		non_coding_transcript_exon	Exon 5 of 8
	FAM24B-CUZD1	NR_037915.1		n.1509C>T		non_coding_transcript_exon	Exon 8 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUZD1	ENST00000392790.6	TSL:1 MANE Select	c.833C>T	p.Ser278Phe	missense	Exon 6 of 9	ENSP00000376540.1	Q86UP6-1
	CUZD1	ENST00000368899.5	TSL:1	n.946C>T		non_coding_transcript_exon	Exon 3 of 6
	CUZD1	ENST00000368900.5	TSL:1	n.*374C>T		non_coding_transcript_exon	Exon 5 of 8	ENSP00000357896.2	A0A0A0MRL2

Frequencies

GnomAD3 genomes AF: 0.0000647 AC: 9 AN: 139206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000106

Gnomad OTH AF: 0.000545

GnomAD2 exomes AF: 0.00000557 AC: 1 AN: 179494 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000795 AC: 110 AN: 1383006 Hom.: 1 Cov.: 31 AF XY: 0.0000904 AC XY: 62 AN XY: 686000

African (AFR) AF: 0.00 AC: 0 AN: 28948

American (AMR) AF: 0.00 AC: 0 AN: 29412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23202

East Asian (EAS) AF: 0.00 AC: 0 AN: 36760

South Asian (SAS) AF: 0.00 AC: 0 AN: 73596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5152

European-Non Finnish (NFE) AF: 0.000101 AC: 109 AN: 1078010

Other (OTH) AF: 0.0000176 AC: 1 AN: 56746

GnomAD4 genome AF: 0.0000647 AC: 9 AN: 139206 Hom.: 0 Cov.: 32 AF XY: 0.0000600 AC XY: 4 AN XY: 66676

African (AFR) AF: 0.0000272 AC: 1 AN: 36830

American (AMR) AF: 0.00 AC: 0 AN: 13218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 4788

South Asian (SAS) AF: 0.00 AC: 0 AN: 4252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.000106 AC: 7 AN: 65800

Other (OTH) AF: 0.000545 AC: 1 AN: 1836

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.75
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.62
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Benign	0.58	T
Sift4G	Benign	0.081	T
Polyphen		0.063	B
Vest4		0.14
MVP		0.82
MPC		0.084
ClinPred		0.10	T
GERP RS		2.1
Varity_R		0.035
gMVP		0.69
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs959019903; hg19: chr10-124595851;