rs2230081

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000227266.10(CTSC):c.825C>T(p.Thr275Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,954 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 7 hom., cov: 32)

Exomes 𝑓: 0.011 ( 112 hom. )

Consequence

CTSC
ENST00000227266.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.07

Publications

4 publications found

Variant links:

Genes affected

CTSC (HGNC:2528): (cathepsin C) This gene encodes a member of the peptidase C1 family and lysosomal cysteine proteinase that appears to be a central coordinator for activation of many serine proteinases in cells of the immune system. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate heavy and light chains that form a disulfide-linked dimer. A portion of the propeptide acts as an intramolecular chaperone for the folding and stabilization of the mature enzyme. This enzyme requires chloride ions for activity and can degrade glucagon. Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre syndrome, an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis. [provided by RefSeq, Nov 2015]

CTSC Gene-Disease associations (from GenCC):

Papillon-Lefevre disease
Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Haim-Munk syndrome
Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
ectodermal dysplasia syndrome
Inheritance: AR Classification: STRONG Submitted by: Illumina
periodontitis, aggressive 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CTSC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.016).

BP6

Variant 11-88296197-G-A is Benign according to our data. Variant chr11-88296197-G-A is described in ClinVar as Benign. ClinVar VariationId is 466229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.08 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00763 (1162/152258) while in subpopulation NFE AF = 0.0121 (820/68034). AF 95% confidence interval is 0.0114. There are 7 homozygotes in GnomAd4. There are 554 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000227266.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSC	NM_001814.6	MANE Select	c.825C>T	p.Thr275Thr	synonymous	Exon 6 of 7	NP_001805.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CTSC	ENST00000227266.10	TSL:1 MANE Select	c.825C>T	p.Thr275Thr	synonymous	Exon 6 of 7	ENSP00000227266.4
CTSC	ENST00000678464.1		c.825C>T	p.Thr275Thr	synonymous	Exon 6 of 7	ENSP00000503046.1
CTSC	ENST00000678506.1		c.786C>T	p.Thr262Thr	synonymous	Exon 6 of 7	ENSP00000503580.1

Frequencies

GnomAD3 genomes

AF:

0.00764

AC:

1162

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00903

AC:

2271

AN:

251448

AF XY:

0.00881

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00645

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0160

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.00880

GnomAD4 exome

AF:

0.0106

AC:

15462

AN:

1461696

Hom.:

112

Cov.:

AF XY:

0.0103

AC XY:

7484

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33470

American (AMR)

AF:

0.00297

AC:

133

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00589

AC:

154

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00313

AC:

270

AN:

86252

European-Finnish (FIN)

AF:

0.0160

AC:

857

AN:

53414

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0121

AC:

13433

AN:

1111866

Other (OTH)

AF:

0.00921

AC:

556

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

836

1673

2509

3346

4182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

478

956

1434

1912

2390

<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:

0.00763

AC:

1162

AN:

152258

Hom.:

Cov.:

AF XY:

0.00744

AC XY:

554

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41530

American (AMR)

AF:

0.00268

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00311

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0148

AC:

157

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0121

AC:

820

AN:

68034

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0100

Hom.:

Bravo

AF:

0.00683

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0102

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Haim-Munk syndrome (1)

Papillon-Lefèvre syndrome (1)

Papillon-Lefèvre syndrome;C1855627:Haim-Munk syndrome;C4551681:Periodontitis, aggressive 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over