rs11019400

Variant names:

• chr11-88337690-A-G
• rs11019400
• NM_001814.6:c.-18T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 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)

ENSG00000288018 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.-18T>C		5_prime_UTR	Exon 1 of 7	NP_001805.4
	CTSC	NM_001114173.3		c.-18T>C		5_prime_UTR	Exon 1 of 4	NP_001107645.1
	CTSC	NM_148170.5		c.-18T>C		5_prime_UTR	Exon 1 of 4	NP_680475.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSC	ENST00000227266.10	TSL:1 MANE Select	c.-18T>C		5_prime_UTR	Exon 1 of 7	ENSP00000227266.4
	CTSC	ENST00000529974.2	TSL:1	c.-18T>C		5_prime_UTR	Exon 1 of 4	ENSP00000433539.1
	CTSC	ENST00000524463.6	TSL:1	c.-18T>C		5_prime_UTR	Exon 1 of 4	ENSP00000432541.1

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

GnomAD2 exomes AF: 0.0715 AC: 11630 AN: 162690 AF XY: 0.0714

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 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

African (AFR) AF: 0.100 AC: 3216 AN: 32090

American (AMR) AF: 0.0573 AC: 2125 AN: 37064

Ashkenazi Jewish (ASJ) AF: 0.0892 AC: 2254 AN: 25280

East Asian (EAS) AF: 0.000218 AC: 8 AN: 36618

South Asian (SAS) AF: 0.0468 AC: 3745 AN: 79964

European-Finnish (FIN) AF: 0.0711 AC: 3510 AN: 49350

Middle Eastern (MID) AF: 0.0705 AC: 402 AN: 5706

European-Non Finnish (NFE) AF: 0.0939 AC: 101814 AN: 1084402

Other (OTH) AF: 0.0776 AC: 4529 AN: 58394

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

African (AFR) AF: 0.101 AC: 4177 AN: 41534

American (AMR) AF: 0.0709 AC: 1085 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0903 AC: 313 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0380 AC: 183 AN: 4820

European-Finnish (FIN) AF: 0.0702 AC: 745 AN: 10606

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0963 AC: 6548 AN: 67984

Other (OTH) AF: 0.0823 AC: 174 AN: 2114

Alfa AF: 0.0874 Hom.: 319

Bravo AF: 0.0904

Asia WGS AF: 0.0250 AC: 90 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Haim-Munk syndrome (1)
-	-	1	not specified (1)
-	-	1	Papillon-Lefèvre syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.61
DANN	Benign	0.41
PhyloP100		-1.5
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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