chr11-88335088-G-GA

Variant names:

• chr11-88335088-G-GA
• rs11326739
• NM_001814.6:c.173-7dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001814.6(CTSC):​c.173-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,037,614 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 29)
  • Exomes 𝑓: 0.19 (1 hom.)
• Consequence: CTSC NM_001814.6 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.410
• Publications: 1 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 11-88335088-G-GA is Benign according to our data. Variant chr11-88335088-G-GA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 306431.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00189 (204/108014) while in subpopulation AFR AF = 0.00362 (107/29534). AF 95% confidence interval is 0.00307. There are 2 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSC	NM_001814.6	c.173-7dupT		splice_region_variant, intron_variant	Intron 1 of 6	ENST00000227266.10	NP_001805.4
CTSC	NM_001114173.3	c.173-7dupT		splice_region_variant, intron_variant	Intron 1 of 3		NP_001107645.1
CTSC	NM_148170.5	c.173-7dupT		splice_region_variant, intron_variant	Intron 1 of 3		NP_680475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10	c.173-7dupT		splice_region_variant, intron_variant	Intron 1 of 6	1	NM_001814.6	ENSP00000227266.4

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 202 AN: 107974 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000554

Gnomad ASJ AF: 0.000806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000285

Gnomad FIN AF: 0.00477

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00348

GnomAD2 exomes AF: 0.136 AC: 17997 AN: 132778 AF XY: 0.133

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.170

Gnomad FIN exome AF: 0.0581

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.186 AC: 173299 AN: 929600 Hom.: 1 Cov.: 16 AF XY: 0.185 AC XY: 85487 AN XY: 462740

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.169 AC: 3711 AN: 21950

American (AMR) AF: 0.140 AC: 4210 AN: 30096

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 3363 AN: 16678

East Asian (EAS) AF: 0.150 AC: 4244 AN: 28258

South Asian (SAS) AF: 0.167 AC: 9141 AN: 54848

European-Finnish (FIN) AF: 0.120 AC: 4206 AN: 35092

Middle Eastern (MID) AF: 0.157 AC: 546 AN: 3476

European-Non Finnish (NFE) AF: 0.195 AC: 136485 AN: 701026

Other (OTH) AF: 0.194 AC: 7393 AN: 38176

⚠️ 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.

GnomAD4 genome AF: 0.00189 AC: 204 AN: 108014 Hom.: 2 Cov.: 29 AF XY: 0.00202 AC XY: 105 AN XY: 52036

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00362 AC: 107 AN: 29534

American (AMR) AF: 0.000553 AC: 6 AN: 10848

Ashkenazi Jewish (ASJ) AF: 0.000806 AC: 2 AN: 2482

East Asian (EAS) AF: 0.000266 AC: 1 AN: 3762

South Asian (SAS) AF: 0.000286 AC: 1 AN: 3496

European-Finnish (FIN) AF: 0.00477 AC: 31 AN: 6500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 180

European-Non Finnish (NFE) AF: 0.00104 AC: 51 AN: 49200

Other (OTH) AF: 0.00346 AC: 5 AN: 1444

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0603 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Papillon-Lefèvre syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Haim-Munk syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

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

Other links and lift over

dbSNP: rs11326739; hg19: chr11-88068256; COSMIC: COSV57056785;