NM_001814.6:c.757+177A>G

Variant names:

• chr11-88300353-T-C
• rs217115
• NM_001814.6:c.757+177A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001814.6(CTSC):​c.757+177A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.883 in 152,240 control chromosomes in the GnomAD database, including 59,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.88 (59597 hom., cov: 32)
• Consequence: CTSC NM_001814.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0590
• Publications: 6 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)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-88300353-T-C is Benign according to our data. Variant chr11-88300353-T-C is described in ClinVar as Benign. ClinVar VariationId is 1287626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSC	NM_001814.6	c.757+177A>G		intron_variant	Intron 5 of 6	ENST00000227266.10	NP_001805.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSC	ENST00000227266.10	c.757+177A>G		intron_variant	Intron 5 of 6	1	NM_001814.6	ENSP00000227266.4

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134340 AN: 152122 Hom.: 59545 Cov.: 32

Gnomad AFR AF: 0.936

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.943

Gnomad FIN AF: 0.898

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.842

Gnomad OTH AF: 0.863

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.883 AC: 134451 AN: 152240 Hom.: 59597 Cov.: 32 AF XY: 0.886 AC XY: 65950 AN XY: 74446

African (AFR) AF: 0.936 AC: 38905 AN: 41548

American (AMR) AF: 0.890 AC: 13617 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2581 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5172 AN: 5178

South Asian (SAS) AF: 0.943 AC: 4545 AN: 4820

European-Finnish (FIN) AF: 0.898 AC: 9512 AN: 10598

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

European-Non Finnish (NFE) AF: 0.842 AC: 57257 AN: 68006

Other (OTH) AF: 0.864 AC: 1829 AN: 2116

Alfa AF: 0.854 Hom.: 7195

Bravo AF: 0.886

Asia WGS AF: 0.969 AC: 3367 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.9
DANN	Benign	0.61
PhyloP100		-0.059
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: rs217115; hg19: chr11-88033521;