Genetic Variant CTSH:c.492+31G>A (chr15-78932341-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004390.5(CTSH):c.492+31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,599,172 control chromosomes in the GnomAD database, including 22,570 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 4383 hom., cov: 32)

Exomes 𝑓: 0.12 ( 18187 hom. )

Consequence

CTSH
NM_004390.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.190

Publications

23 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004390.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CTSH	NM_004390.5	MANE Select	c.492+31G>A	intron	N/A	NP_004381.2
CTSH	NM_001411095.1		c.378+31G>A	intron	N/A	NP_001398024.1	E9PKT6
CTSH	NM_001319137.2		c.-446+31G>A	intron	N/A	NP_001306066.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CTSH	ENST00000220166.10	TSL:1 MANE Select	c.492+31G>A	intron	N/A	ENSP00000220166.6	P09668
CTSH	ENST00000615999.5	TSL:1	c.492+31G>A	intron	N/A	ENSP00000483303.2	A0A087X0D5
CTSH	ENST00000527715.6	TSL:1	n.540+31G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

29872

AN:

152036

Hom.:

4374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.341

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.0932

Gnomad EAS

AF:

0.629

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.0834

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0966

Gnomad OTH

AF:

0.185

GnomAD2 exomes

AF:

0.178

AC:

44536

AN:

250006

AF XY:

0.163

show subpopulations

Gnomad AFR exome

AF:

0.346

Gnomad AMR exome

AF:

0.283

Gnomad ASJ exome

AF:

0.0967

Gnomad EAS exome

AF:

0.646

Gnomad FIN exome

AF:

0.0865

Gnomad NFE exome

AF:

0.0972

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.122

AC:

177211

AN:

1447018

Hom.:

18187

Cov.:

AF XY:

0.120

AC XY:

86367

AN XY:

720782

show subpopulations

African (AFR)

AF:

0.347

AC:

11470

AN:

33036

American (AMR)

AF:

0.285

AC:

12704

AN:

44580

Ashkenazi Jewish (ASJ)

AF:

0.0966

AC:

2512

AN:

26016

East Asian (EAS)

AF:

0.612

AC:

24238

AN:

39590

South Asian (SAS)

AF:

0.0918

AC:

7889

AN:

85956

European-Finnish (FIN)

AF:

0.0872

AC:

4649

AN:

53328

Middle Eastern (MID)

AF:

0.106

AC:

610

AN:

5740

European-Non Finnish (NFE)

AF:

0.0951

AC:

104465

AN:

1098866

Other (OTH)

AF:

0.145

AC:

8674

AN:

59906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

6042

12085

18127

24170

30212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4258

8516

12774

17032

21290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.197

AC:

29905

AN:

152154

Hom.:

4383

Cov.:

AF XY:

0.198

AC XY:

14765

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.341

AC:

14144

AN:

41488

American (AMR)

AF:

0.245

AC:

3752

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0932

AC:

323

AN:

3466

East Asian (EAS)

AF:

0.628

AC:

3244

AN:

5166

South Asian (SAS)

AF:

0.107

AC:

517

AN:

4824

European-Finnish (FIN)

AF:

0.0834

AC:

885

AN:

10612

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0966

AC:

6571

AN:

67988

Other (OTH)

AF:

0.185

AC:

391

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1105

2210

3316

4421

5526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

284

568

852

1136

1420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.135

Hom.:

5737

Bravo

AF:

0.220

Asia WGS

AF:

0.330

AC:

1149

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.6

(source)

DANN

Benign

0.71

PhyloP100

-0.19

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over