11-88335088-G-A

Variant names:

• chr11-88335088-G-A
• rs201763299
• NM_001814.6:c.173-6C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001814.6(CTSC):​c.173-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,115,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0081 (0 hom., cov: 26)
  • Exomes 𝑓: 0.026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CTSC NM_001814.6 splice_region, intron
• Scores: Splicing: ADA: 0.00004712
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26
• Publications: 0 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):

• Haim-Munk syndrome

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Papillon-Lefevre disease

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0887) population. However there is too low homozygotes in high coverage region: (expected more than 195, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 11-88335088-G-A is Benign according to our data. Variant chr11-88335088-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 466226.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001814.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSC	NM_001814.6	MANE Select	c.173-6C>T		splice_region intron	N/A	NP_001805.4	P53634-1
	CTSC	NM_001114173.3		c.173-6C>T		splice_region intron	N/A	NP_001107645.1	P53634-3
	CTSC	NM_148170.5		c.173-6C>T		splice_region intron	N/A	NP_680475.1	P53634-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSC	ENST00000227266.10	TSL:1 MANE Select	c.173-6C>T		splice_region intron	N/A	ENSP00000227266.4	P53634-1
	CTSC	ENST00000529974.2	TSL:1	c.173-6C>T		splice_region intron	N/A	ENSP00000433539.1	P53634-3
	CTSC	ENST00000524463.6	TSL:1	c.173-6C>T		splice_region intron	N/A	ENSP00000432541.1	P53634-2

Frequencies

GnomAD3 genomes AF: 0.00806 AC: 864 AN: 107132 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00527

Gnomad AMI AF: 0.0125

Gnomad AMR AF: 0.00584

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00535

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.0382

Gnomad MID AF: 0.00526

Gnomad NFE AF: 0.00719

Gnomad OTH AF: 0.00563

GnomAD2 exomes AF: 0.166 AC: 22046 AN: 132778 AF XY: 0.174

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.0265 AC: 29518 AN: 1115146 Hom.: 0 Cov.: 22 AF XY: 0.0311 AC XY: 17515 AN XY: 562334

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

African (AFR) AF: 0.0274 AC: 706 AN: 25776

American (AMR) AF: 0.0913 AC: 3264 AN: 35758

Ashkenazi Jewish (ASJ) AF: 0.0570 AC: 1237 AN: 21720

East Asian (EAS) AF: 0.0347 AC: 1216 AN: 35092

South Asian (SAS) AF: 0.0696 AC: 4975 AN: 71530

European-Finnish (FIN) AF: 0.0962 AC: 4090 AN: 42522

Middle Eastern (MID) AF: 0.0843 AC: 348 AN: 4130

European-Non Finnish (NFE) AF: 0.0153 AC: 12706 AN: 831262

Other (OTH) AF: 0.0206 AC: 976 AN: 47356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00812 AC: 870 AN: 107170 Hom.: 0 Cov.: 26 AF XY: 0.00894 AC XY: 462 AN XY: 51654

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

African (AFR) AF: 0.00533 AC: 156 AN: 29278

American (AMR) AF: 0.00583 AC: 63 AN: 10802

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 5 AN: 2464

East Asian (EAS) AF: 0.00563 AC: 21 AN: 3732

South Asian (SAS) AF: 0.00288 AC: 10 AN: 3474

European-Finnish (FIN) AF: 0.0382 AC: 247 AN: 6468

Middle Eastern (MID) AF: 0.00556 AC: 1 AN: 180

European-Non Finnish (NFE) AF: 0.00720 AC: 351 AN: 48782

Other (OTH) AF: 0.00630 AC: 9 AN: 1428

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0140 Hom.: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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	-0.73
CADD	Benign	2.2
DANN	Benign	0.64
PhyloP100		1.3
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0
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: rs201763299; hg19: chr11-88068256; COSMIC: COSV57056754;