chr11-88337690-A-G

Position:

chr11-88337690-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.47

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Effect	#exon/exons	MANE	Protein
CTSC	NM_001814.6 linkuse as main transcript	c.-18T>C	5_prime_UTR_variant	1/7	ENST00000227266.10	NP_001805.4
CTSC	NM_001114173.3 linkuse as main transcript	c.-18T>C	5_prime_UTR_variant	1/4		NP_001107645.1
CTSC	NM_148170.5 linkuse as main transcript	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 linkuse as main transcript	c.-18T>C		5_prime_UTR_variant	1/7	1	NM_001814.6	ENSP00000227266	P1	P53634-1

Frequencies

GnomAD3 genomes

AF:

0.0881

AC:

13404

AN:

152098

Hom.:

628

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0851

AC XY:

59193

AN XY:

695754

show subpopulations

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.:

AF XY:

0.0845

AC XY:

6289

AN XY:

74426

show subpopulations

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:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over