NM_001814.6:c.173-7delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001814.6(CTSC):​c.173-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,133,870 control chromosomes in the GnomAD database, including 593 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.089 ( 376 hom., cov: 29)
Exomes 𝑓: 0.12 ( 217 hom. )

Consequence

CTSC
NM_001814.6 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.410

Publications

1 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6
Variant 11-88335088-GA-G is Benign according to our data. Variant chr11-88335088-GA-G is described in ClinVar as [Benign]. Clinvar id is 402573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTSCNM_001814.6 linkc.173-7delT splice_region_variant, intron_variant Intron 1 of 6 ENST00000227266.10 NP_001805.4 P53634-1
CTSCNM_001114173.3 linkc.173-7delT splice_region_variant, intron_variant Intron 1 of 3 NP_001107645.1 P53634-3
CTSCNM_148170.5 linkc.173-7delT splice_region_variant, intron_variant Intron 1 of 3 NP_680475.1 P53634-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTSCENST00000227266.10 linkc.173-7delT splice_region_variant, intron_variant Intron 1 of 6 1 NM_001814.6 ENSP00000227266.4 P53634-1

Frequencies

GnomAD3 genomes
AF:
0.0892
AC:
9633
AN:
107956
Hom.:
374
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.130
Gnomad AMI
AF:
0.0387
Gnomad AMR
AF:
0.102
Gnomad ASJ
AF:
0.00886
Gnomad EAS
AF:
0.141
Gnomad SAS
AF:
0.0867
Gnomad FIN
AF:
0.123
Gnomad MID
AF:
0.0417
Gnomad NFE
AF:
0.0589
Gnomad OTH
AF:
0.0774
GnomAD2 exomes
AF:
0.176
AC:
23316
AN:
132778
AF XY:
0.173
show subpopulations
Gnomad AFR exome
AF:
0.200
Gnomad AMR exome
AF:
0.206
Gnomad ASJ exome
AF:
0.0926
Gnomad EAS exome
AF:
0.192
Gnomad FIN exome
AF:
0.207
Gnomad NFE exome
AF:
0.164
Gnomad OTH exome
AF:
0.162
GnomAD4 exome
AF:
0.118
AC:
120938
AN:
1025878
Hom.:
217
Cov.:
16
AF XY:
0.116
AC XY:
59814
AN XY:
515860
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.158
AC:
3784
AN:
23920
American (AMR)
AF:
0.154
AC:
5088
AN:
33000
Ashkenazi Jewish (ASJ)
AF:
0.0739
AC:
1425
AN:
19292
East Asian (EAS)
AF:
0.192
AC:
6085
AN:
31704
South Asian (SAS)
AF:
0.117
AC:
7738
AN:
66318
European-Finnish (FIN)
AF:
0.160
AC:
6214
AN:
38790
Middle Eastern (MID)
AF:
0.0980
AC:
366
AN:
3734
European-Non Finnish (NFE)
AF:
0.111
AC:
85105
AN:
766132
Other (OTH)
AF:
0.119
AC:
5133
AN:
42988
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.354
Heterozygous variant carriers
0
7513
15026
22539
30052
37565
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
3242
6484
9726
12968
16210
<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:
0.0894
AC:
9652
AN:
107992
Hom.:
376
Cov.:
29
AF XY:
0.0931
AC XY:
4845
AN XY:
52016
show subpopulations
African (AFR)
AF:
0.130
AC:
3844
AN:
29534
American (AMR)
AF:
0.102
AC:
1108
AN:
10854
Ashkenazi Jewish (ASJ)
AF:
0.00886
AC:
22
AN:
2484
East Asian (EAS)
AF:
0.142
AC:
532
AN:
3758
South Asian (SAS)
AF:
0.0870
AC:
304
AN:
3494
European-Finnish (FIN)
AF:
0.123
AC:
801
AN:
6498
Middle Eastern (MID)
AF:
0.0440
AC:
8
AN:
182
European-Non Finnish (NFE)
AF:
0.0589
AC:
2897
AN:
49180
Other (OTH)
AF:
0.0792
AC:
114
AN:
1440
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
434
869
1303
1738
2172
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
102
204
306
408
510
<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:
0.0438
Hom.:
0

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Mar 28, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Papillon-Lefèvre syndrome;C1855627:Haim-Munk syndrome;C4551681:Periodontitis, aggressive 1 Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
May 04, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
-0.41
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs11326739; hg19: chr11-88068256; API