rs3888798

Variant names:

• chr11-88294041-T-C
• rs3888798
• NM_001814.6:c.1357A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-88294041-T-C
• chr11-88294041-T-A
• chr11-88294041-T-G

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.1357A>G​(p.Ile453Val) variant causes a missense change. The variant allele was found at a frequency of 0.0486 in 1,613,916 control chromosomes in the GnomAD database, including 2,560 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (292 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2268 hom.)
• Consequence: CTSC NM_001814.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 6.14
• Publications: 37 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 (MetaRNN=0.004112333).
• BP6: Variant 11-88294041-T-C is Benign according to our data. Variant chr11-88294041-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0987 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.1357A>G	p.Ile453Val	missense	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.1357A>G	p.Ile453Val	missense	Exon 7 of 7	ENSP00000227266.4	P53634-1
	CTSC	ENST00000880823.1		c.1357A>G	p.Ile453Val	missense	Exon 8 of 8	ENSP00000550882.1
	CTSC	ENST00000880825.1		c.1345A>G	p.Ile449Val	missense	Exon 7 of 7	ENSP00000550884.1

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8833 AN: 152058 Hom.: 294 Cov.: 32

Gnomad AFR AF: 0.0699

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0723

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.0732

Gnomad FIN AF: 0.0912

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0451

GnomAD2 exomes AF: 0.0614 AC: 15419 AN: 251062 AF XY: 0.0603

Gnomad AFR exome AF: 0.0699

Gnomad AMR exome AF: 0.0878

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.0896

Gnomad FIN exome AF: 0.0945

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0449

GnomAD4 exome AF: 0.0476 AC: 69624 AN: 1461740 Hom.: 2268 Cov.: 31 AF XY: 0.0478 AC XY: 34789 AN XY: 727188

African (AFR) AF: 0.0665 AC: 2225 AN: 33466

American (AMR) AF: 0.0845 AC: 3777 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00708 AC: 185 AN: 26136

East Asian (EAS) AF: 0.129 AC: 5105 AN: 39698

South Asian (SAS) AF: 0.0830 AC: 7155 AN: 86252

European-Finnish (FIN) AF: 0.0915 AC: 4884 AN: 53400

Middle Eastern (MID) AF: 0.0274 AC: 158 AN: 5768

European-Non Finnish (NFE) AF: 0.0391 AC: 43530 AN: 1111930

Other (OTH) AF: 0.0431 AC: 2605 AN: 60390

GnomAD4 genome AF: 0.0582 AC: 8851 AN: 152176 Hom.: 292 Cov.: 32 AF XY: 0.0609 AC XY: 4527 AN XY: 74392

African (AFR) AF: 0.0699 AC: 2900 AN: 41516

American (AMR) AF: 0.0726 AC: 1109 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.106 AC: 549 AN: 5178

South Asian (SAS) AF: 0.0735 AC: 354 AN: 4818

European-Finnish (FIN) AF: 0.0912 AC: 965 AN: 10586

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0416 AC: 2828 AN: 68008

Other (OTH) AF: 0.0470 AC: 99 AN: 2106

Alfa AF: 0.0460 Hom.: 834

Bravo AF: 0.0556

TwinsUK AF: 0.0405 AC: 150

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.0686 AC: 302

ESP6500EA AF: 0.0386 AC: 332

ExAC AF: 0.0615 AC: 7464

Asia WGS AF: 0.0920 AC: 320 AN: 3478

EpiCase AF: 0.0363

EpiControl AF: 0.0317

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Haim-Munk syndrome (1)
-	-	1	not provided (1)
-	-	1	Papillon-Lefèvre syndrome (1)
-	-	1	Papillon-Lefèvre syndrome;C1855627:Haim-Munk syndrome;C4551681:Periodontitis, aggressive 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.47	N
PhyloP100		6.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.015	D
Sift4G	Benign	0.13	T
Polyphen		0.44	B
Vest4		0.17
MPC		0.10
ClinPred		0.030	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.59
Mutation Taster		=69/31	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: rs3888798; hg19: chr11-88027209; COSMIC: COSV57056940; COSMIC: COSV57056940;