chr11-88293727-T-C

Variant names:

• chr11-88293727-T-C
• rs146045268
• NM_001814.6:c.*279A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001814.6(CTSC):​c.*279A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 433,676 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: CTSC NM_001814.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.563
• 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):

• Haim-Munk syndrome

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Papillon-Lefevre disease

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-88293727-T-C is Benign according to our data. Variant chr11-88293727-T-C is described in ClinVar as Benign. ClinVar VariationId is 306415.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00475 (723/152348) while in subpopulation AFR AF = 0.0164 (683/41582). AF 95% confidence interval is 0.0154. There are 7 homozygotes in GnomAd4. There are 349 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 Unknown,AR gene

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.*279A>G		3_prime_UTR	Exon 7 of 7	NP_001805.4	P53634-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSC	ENST00000227266.10	TSL:1 MANE Select	c.*279A>G		3_prime_UTR	Exon 7 of 7	ENSP00000227266.4	P53634-1
	CTSC	ENST00000880823.1		c.*279A>G		3_prime_UTR	Exon 8 of 8	ENSP00000550882.1
	CTSC	ENST00000880825.1		c.*279A>G		3_prime_UTR	Exon 7 of 7	ENSP00000550884.1

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 721 AN: 152230 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.000555 AC: 156 AN: 281328 Hom.: 0 Cov.: 0 AF XY: 0.000441 AC XY: 65 AN XY: 147426

African (AFR) AF: 0.0144 AC: 134 AN: 9336

American (AMR) AF: 0.000523 AC: 6 AN: 11480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8852

East Asian (EAS) AF: 0.00 AC: 0 AN: 18370

South Asian (SAS) AF: 0.0000350 AC: 1 AN: 28568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1246

European-Non Finnish (NFE) AF: 0.0000350 AC: 6 AN: 171484

Other (OTH) AF: 0.000545 AC: 9 AN: 16522

GnomAD4 genome AF: 0.00475 AC: 723 AN: 152348 Hom.: 7 Cov.: 32 AF XY: 0.00468 AC XY: 349 AN XY: 74502

African (AFR) AF: 0.0164 AC: 683 AN: 41582

American (AMR) AF: 0.00176 AC: 27 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00408 Hom.: 1

Bravo AF: 0.00531

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Haim-Munk syndrome (1)
-	-	1	Papillon-Lefèvre syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.74
PhyloP100		-0.56
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

Other links and lift over

dbSNP: rs146045268; hg19: chr11-88026895;