11-88335088-GAAAA-GAA

Variant names:

• chr11-88335088-GAA-G
• rs11326739
• NM_001814.6:c.173-8_173-7delTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001814.6(CTSC):​c.173-8_173-7delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,219,114 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000093 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00099 (0 hom.)
• Consequence: CTSC NM_001814.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.633
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 11-88335088-GAA-G is Benign according to our data. Variant chr11-88335088-GAA-G is described in ClinVar as Benign. ClinVar VariationId is 2930306.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSC	NM_001814.6	MANE Select	c.173-8_173-7delTT		splice_region intron	N/A	NP_001805.4
	CTSC	NM_001114173.3		c.173-8_173-7delTT		splice_region intron	N/A	NP_001107645.1
	CTSC	NM_148170.5		c.173-8_173-7delTT		splice_region intron	N/A	NP_680475.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSC	ENST00000227266.10	TSL:1 MANE Select	c.173-8_173-7delTT		splice_region intron	N/A	ENSP00000227266.4
	CTSC	ENST00000529974.2	TSL:1	c.173-8_173-7delTT		splice_region intron	N/A	ENSP00000433539.1
	CTSC	ENST00000524463.6	TSL:1	c.173-8_173-7delTT		splice_region intron	N/A	ENSP00000432541.1

Frequencies

GnomAD3 genomes AF: 0.00000925 AC: 1 AN: 108094 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00136 AC: 181 AN: 132778 AF XY: 0.00124

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.000805

Gnomad EAS exome AF: 0.000964

Gnomad FIN exome AF: 0.00235

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000990 AC: 1100 AN: 1111020 Hom.: 0 AF XY: 0.000881 AC XY: 494 AN XY: 560576

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

African (AFR) AF: 0.00156 AC: 40 AN: 25696

American (AMR) AF: 0.00131 AC: 47 AN: 35870

Ashkenazi Jewish (ASJ) AF: 0.000277 AC: 6 AN: 21698

East Asian (EAS) AF: 0.00114 AC: 40 AN: 34960

South Asian (SAS) AF: 0.000541 AC: 39 AN: 72024

European-Finnish (FIN) AF: 0.00103 AC: 44 AN: 42626

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.00103 AC: 851 AN: 826820

Other (OTH) AF: 0.000678 AC: 32 AN: 47190

⚠️ 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 AF: 0.00000925 AC: 1 AN: 108094 Hom.: 0 Cov.: 29 AF XY: 0.0000192 AC XY: 1 AN XY: 52066

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

African (AFR) AF: 0.00 AC: 0 AN: 29484

American (AMR) AF: 0.00 AC: 0 AN: 10852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2486

East Asian (EAS) AF: 0.00 AC: 0 AN: 3774

South Asian (SAS) AF: 0.00 AC: 0 AN: 3510

European-Finnish (FIN) AF: 0.000154 AC: 1 AN: 6508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 49282

Other (OTH) AF: 0.00 AC: 0 AN: 1438

⚠️ 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: 0.000474 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CTSC-related disorder (1)
-	-	1	Papillon-Lefèvre syndrome;C1855627:Haim-Munk syndrome;C4551681:Periodontitis, aggressive 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63
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: COSV57058130;