rs11326739

Variant names:

• chr11-88335088-GAAAA-G
• rs11326739
• NM_001814.6:c.173-10_173-7delTTTT

Your query was ambiguous. Multiple possible variants found:

• chr11-88335088-GAAAA-G
• chr11-88335088-GAAAA-GA
• chr11-88335088-GAAAA-GAA
• chr11-88335088-GAAAA-GAAA
• chr11-88335088-GAAAA-GAAAAA
• chr11-88335088-GAAAA-GAAAAAA
• chr11-88335088-GAAAA-GAAAAAAA
• chr11-88335088-GAAAA-GAAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001814.6(CTSC):​c.173-10_173-7delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,120,460 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CTSC NM_001814.6 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.82
• 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):

• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-88335088-GAAAA-G is Benign according to our data. Variant chr11-88335088-GAAAA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2951257.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.173-10_173-7delTTTT		splice_region intron	N/A	NP_001805.4
	CTSC	NM_001114173.3		c.173-10_173-7delTTTT		splice_region intron	N/A	NP_001107645.1
	CTSC	NM_148170.5		c.173-10_173-7delTTTT		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.173-10_173-7delTTTT		splice_region intron	N/A	ENSP00000227266.4
	CTSC	ENST00000529974.2	TSL:1	c.173-10_173-7delTTTT		splice_region intron	N/A	ENSP00000433539.1
	CTSC	ENST00000524463.6	TSL:1	c.173-10_173-7delTTTT		splice_region intron	N/A	ENSP00000432541.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000357 AC: 4 AN: 1120460 Hom.: 0 AF XY: 0.00000354 AC XY: 2 AN XY: 565232

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

African (AFR) AF: 0.0000386 AC: 1 AN: 25898

American (AMR) AF: 0.00 AC: 0 AN: 36072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21864

East Asian (EAS) AF: 0.00 AC: 0 AN: 35242

South Asian (SAS) AF: 0.0000138 AC: 1 AN: 72324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4166

European-Non Finnish (NFE) AF: 0.00000240 AC: 2 AN: 834348

Other (OTH) AF: 0.00 AC: 0 AN: 47584

⚠️ 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 Cov.: 29

ClinVar

ClinVar submissions as Germline

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
PhyloP100		1.8

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;