chr15-78922186-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_004390.5(CTSH):c.952G>A(p.Gly318Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000386 in 1,582,188 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: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

CTSH
NM_004390.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.44

Publications

0 publications found

Variant links:

Genes affected

CTSH (HGNC:2535): (cathepsin H) The protein encoded by this gene is a lysosomal cysteine proteinase important in the overall degradation of lysosomal proteins. It is composed of a dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. The encoded protein, which belongs to the peptidase C1 protein family, can act both as an aminopeptidase and as an endopeptidase. Increased expression of this gene has been correlated with malignant progression of prostate tumors. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

CTSH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSH	NM_004390.5 link	c.952G>A	p.Gly318Arg	missense_variant	Exon 12 of 12	ENST00000220166.10	NP_004381.2	P09668
CTSH	NM_001411095.1 link	c.838G>A	p.Gly280Arg	missense_variant	Exon 12 of 12		NP_001398024.1
CTSH	NM_001319137.2 link	c.550G>A	p.Gly184Arg	missense_variant	Exon 13 of 13		NP_001306066.1
CTSH	XM_017021951.2 link	c.898G>A	p.Gly300Arg	missense_variant	Exon 13 of 13		XP_016877440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSH	ENST00000220166.10 link	c.952G>A	p.Gly318Arg	missense_variant	Exon 12 of 12	1	NM_004390.5	ENSP00000220166.6		P09668

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000502

AC:

AN:

199072

AF XY:

0.0000375

show subpopulations

Gnomad AFR exome

AF:

0.0000836

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000329

Gnomad FIN exome

AF:

0.0000583

Gnomad NFE exome

AF:

0.0000348

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000350

AC:

AN:

1429998

Hom.:

Cov.:

AF XY:

0.0000311

AC XY:

AN XY:

708328

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

32986

American (AMR)

AF:

0.00

AC:

AN:

39996

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25558

East Asian (EAS)

AF:

0.000130

AC:

AN:

38366

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81518

European-Finnish (FIN)

AF:

0.0000197

AC:

AN:

50860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4756

European-Non Finnish (NFE)

AF:

0.0000328

AC:

AN:

1096818

Other (OTH)

AF:

0.0000507

AC:

AN:

59140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000583

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 30, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.952G>A (p.G318R) alteration is located in exon 12 (coding exon 12) of the CTSH gene. This alteration results from a G to A substitution at nucleotide position 952, causing the glycine (G) at amino acid position 318 to be replaced by an arginine (R). 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

0.64

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-0.65

MutationAssessor

Pathogenic

3.1

M;.

PhyloP100

6.4

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.1

D;.

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.85

MutPred

0.77

Gain of solvent accessibility (P = 0.0171);.;

MVP

0.23

MPC

0.67

ClinPred

0.82

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.80

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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chr15-78922186-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over