rs217116

Variant names:

• chr11-88300493-A-G
• rs217116
• NM_001814.6:c.757+37T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-88300493-A-G
• chr11-88300493-A-C
• chr11-88300493-A-T

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.757+37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.862 in 1,315,360 control chromosomes in the GnomAD database, including 490,083 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (58622 hom., cov: 32)
  • Exomes 𝑓: 0.86 (431461 hom.)
• Consequence: CTSC NM_001814.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.206
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-88300493-A-G is Benign according to our data. Variant chr11-88300493-A-G is described in ClinVar as Benign. ClinVar VariationId is 258191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 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.757+37T>C		intron	N/A	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.757+37T>C		intron	N/A	ENSP00000227266.4	P53634-1
	CTSC	ENST00000880823.1		c.757+37T>C		intron	N/A	ENSP00000550882.1
	CTSC	ENST00000880825.1		c.745+37T>C		intron	N/A	ENSP00000550884.1

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133259 AN: 152048 Hom.: 58571 Cov.: 32

Gnomad AFR AF: 0.913

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.744

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.942

Gnomad FIN AF: 0.897

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.842

Gnomad OTH AF: 0.857

GnomAD2 exomes AF: 0.884 AC: 219920 AN: 248858 AF XY: 0.883

Gnomad AFR exome AF: 0.916

Gnomad AMR exome AF: 0.917

Gnomad ASJ exome AF: 0.752

Gnomad EAS exome AF: 0.996

Gnomad FIN exome AF: 0.890

Gnomad NFE exome AF: 0.847

Gnomad OTH exome AF: 0.864

GnomAD4 exome AF: 0.860 AC: 1000353 AN: 1163194 Hom.: 431461 Cov.: 15 AF XY: 0.862 AC XY: 511106 AN XY: 593134

African (AFR) AF: 0.912 AC: 25042 AN: 27462

American (AMR) AF: 0.915 AC: 40522 AN: 44266

Ashkenazi Jewish (ASJ) AF: 0.758 AC: 18316 AN: 24164

East Asian (EAS) AF: 0.998 AC: 38181 AN: 38250

South Asian (SAS) AF: 0.940 AC: 75151 AN: 79926

European-Finnish (FIN) AF: 0.888 AC: 47158 AN: 53100

Middle Eastern (MID) AF: 0.833 AC: 4334 AN: 5204

European-Non Finnish (NFE) AF: 0.843 AC: 708385 AN: 840204

Other (OTH) AF: 0.855 AC: 43264 AN: 50618

GnomAD4 genome AF: 0.876 AC: 133369 AN: 152166 Hom.: 58622 Cov.: 32 AF XY: 0.880 AC XY: 65440 AN XY: 74400

African (AFR) AF: 0.913 AC: 37920 AN: 41518

American (AMR) AF: 0.888 AC: 13577 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 2581 AN: 3470

East Asian (EAS) AF: 0.995 AC: 5161 AN: 5188

South Asian (SAS) AF: 0.942 AC: 4535 AN: 4816

European-Finnish (FIN) AF: 0.897 AC: 9509 AN: 10596

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.842 AC: 57247 AN: 67982

Other (OTH) AF: 0.859 AC: 1808 AN: 2106

Alfa AF: 0.852 Hom.: 179192

Bravo AF: 0.878

Asia WGS AF: 0.958 AC: 3329 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.51
DANN	Benign	0.48
PhyloP100		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs217116; hg19: chr11-88033661;