rs11019400

Positions:

• chr11-88337690-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001814.6(CTSC):​c.-18T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0865 in 1,561,084 control chromosomes in the GnomAD database, including 6,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (628 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5627 hom.)
• Consequence: CTSC NM_001814.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.47

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-88337690-A-G is Benign according to our data. Variant chr11-88337690-A-G is described in ClinVar as [Benign]. Clinvar id is 258188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSC	NM_001814.6	c.-18T>C		5_prime_UTR_variant	1/7	ENST00000227266.10	NP_001805.4
CTSC	NM_001114173.3	c.-18T>C		5_prime_UTR_variant	1/4		NP_001107645.1
CTSC	NM_148170.5	c.-18T>C		5_prime_UTR_variant	1/4		NP_680475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10	c.-18T>C		5_prime_UTR_variant	1/7	1	NM_001814.6	ENSP00000227266	P1

Frequencies

GnomAD3 genomes AF: 0.0881 AC: 13404 AN: 152098 Hom.: 628 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.0903

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0377

Gnomad FIN AF: 0.0702

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0963

Gnomad OTH AF: 0.0837

GnomAD3 exomes AF: 0.0715 AC: 11630 AN: 162690 Hom.: 501 AF XY: 0.0714 AC XY: 6222 AN XY: 87188

Gnomad AFR exome AF: 0.0976

Gnomad AMR exome AF: 0.0541

Gnomad ASJ exome AF: 0.0852

Gnomad EAS exome AF: 0.000248

Gnomad SAS exome AF: 0.0467

Gnomad FIN exome AF: 0.0688

Gnomad NFE exome AF: 0.0955

Gnomad OTH exome AF: 0.0816

GnomAD4 exome AF: 0.0863 AC: 121603 AN: 1408868 Hom.: 5627 Cov.: 32 AF XY: 0.0851 AC XY: 59193 AN XY: 695754

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.0573

Gnomad4 ASJ exome AF: 0.0892

Gnomad4 EAS exome AF: 0.000218

Gnomad4 SAS exome AF: 0.0468

Gnomad4 FIN exome AF: 0.0711

Gnomad4 NFE exome AF: 0.0939

Gnomad4 OTH exome AF: 0.0776

GnomAD4 genome AF: 0.0881 AC: 13414 AN: 152216 Hom.: 628 Cov.: 32 AF XY: 0.0845 AC XY: 6289 AN XY: 74426

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0709

Gnomad4 ASJ AF: 0.0903

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0380

Gnomad4 FIN AF: 0.0702

Gnomad4 NFE AF: 0.0963

Gnomad4 OTH AF: 0.0823

Alfa AF: 0.0916 Hom.: 218

Bravo AF: 0.0904

Asia WGS AF: 0.0250 AC: 90 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Papillon-Lefèvre syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Haim-Munk syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.61
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

LitVar

Other links and lift over

dbSNP: rs11019400; hg19: chr11-88070858; COSMIC: COSV57059351;