20-58997654-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001336.4(CTSZ):c.587T>C(p.Leu196Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00711 in 1,608,464 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (53 hom.)
• Consequence: CTSZ NM_001336.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.49

Genes affected

CTSZ (HGNC:2547): (cathepsin Z) The protein encoded by this gene is a lysosomal cysteine proteinase and member of the peptidase C1 family. It exhibits both carboxy-monopeptidase and carboxy-dipeptidase activities. The encoded protein has also been known as cathepsin X and cathepsin P. This gene is expressed ubiquitously in cancer cell lines and primary tumors and, like other members of this family, may be involved in tumorigenesis. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011101931).
• BP6: Variant 20-58997654-A-G is Benign according to our data. Variant chr20-58997654-A-G is described in ClinVar as [Benign]. Clinvar id is 779289.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSZ	NM_001336.4	c.587T>C	p.Leu196Pro	missense_variant	4/6	ENST00000217131.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSZ	ENST00000217131.6	c.587T>C	p.Leu196Pro	missense_variant	4/6	1	NM_001336.4	P1

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 761 AN: 152150 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00488 AC: 1202 AN: 246222 Hom.: 4 AF XY: 0.00513 AC XY: 683 AN XY: 133184

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00274

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00541

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00748

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00733 AC: 10679 AN: 1456196 Hom.: 53 Cov.: 35 AF XY: 0.00727 AC XY: 5263 AN XY: 724036

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00258

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00518

Gnomad4 FIN exome AF: 0.00399

Gnomad4 NFE exome AF: 0.00846

Gnomad4 OTH exome AF: 0.00783

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152268 Hom.: 6 Cov.: 32 AF XY: 0.00501 AC XY: 373 AN XY: 74446

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00795

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00659 Hom.: 4

Bravo AF: 0.00472

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00497 AC: 603

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.036	D
Polyphen		0.85	P
Vest4		0.46
MVP		0.73
MPC		1.1
ClinPred		0.023	T
GERP RS		5.7
Varity_R		0.89
gMVP		0.94

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: rs199825459; hg19: chr20-57572709; COSMIC: COSV99036807; COSMIC: COSV99036807;