NM_001814.6:c.173-7delT

Variant names:

• chr11-88335088-GA-G
• rs11326739
• NM_001814.6:c.173-7delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001814.6(CTSC):​c.173-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,133,870 control chromosomes in the GnomAD database, including 593 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (376 hom., cov: 29)
  • Exomes 𝑓: 0.12 (217 hom.)
• Consequence: CTSC NM_001814.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.410
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 11-88335088-GA-G is Benign according to our data. Variant chr11-88335088-GA-G is described in ClinVar as Benign. ClinVar VariationId is 402573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSC	NM_001814.6	MANE Select	c.173-7delT		splice_region intron	N/A	NP_001805.4
	CTSC	NM_001114173.3		c.173-7delT		splice_region intron	N/A	NP_001107645.1
	CTSC	NM_148170.5		c.173-7delT		splice_region intron	N/A	NP_680475.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSC	ENST00000227266.10	TSL:1 MANE Select	c.173-7delT		splice_region intron	N/A	ENSP00000227266.4
	CTSC	ENST00000529974.2	TSL:1	c.173-7delT		splice_region intron	N/A	ENSP00000433539.1
	CTSC	ENST00000524463.6	TSL:1	c.173-7delT		splice_region intron	N/A	ENSP00000432541.1

Frequencies

GnomAD3 genomes AF: 0.0892 AC: 9633 AN: 107956 Hom.: 374 Cov.: 29

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0387

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.00886

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.0867

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.0589

Gnomad OTH AF: 0.0774

GnomAD2 exomes AF: 0.176 AC: 23316 AN: 132778 AF XY: 0.173

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.0926

Gnomad EAS exome AF: 0.192

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.118 AC: 120938 AN: 1025878 Hom.: 217 Cov.: 16 AF XY: 0.116 AC XY: 59814 AN XY: 515860

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.158 AC: 3784 AN: 23920

American (AMR) AF: 0.154 AC: 5088 AN: 33000

Ashkenazi Jewish (ASJ) AF: 0.0739 AC: 1425 AN: 19292

East Asian (EAS) AF: 0.192 AC: 6085 AN: 31704

South Asian (SAS) AF: 0.117 AC: 7738 AN: 66318

European-Finnish (FIN) AF: 0.160 AC: 6214 AN: 38790

Middle Eastern (MID) AF: 0.0980 AC: 366 AN: 3734

European-Non Finnish (NFE) AF: 0.111 AC: 85105 AN: 766132

Other (OTH) AF: 0.119 AC: 5133 AN: 42988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0894 AC: 9652 AN: 107992 Hom.: 376 Cov.: 29 AF XY: 0.0931 AC XY: 4845 AN XY: 52016

African (AFR) AF: 0.130 AC: 3844 AN: 29534

American (AMR) AF: 0.102 AC: 1108 AN: 10854

Ashkenazi Jewish (ASJ) AF: 0.00886 AC: 22 AN: 2484

East Asian (EAS) AF: 0.142 AC: 532 AN: 3758

South Asian (SAS) AF: 0.0870 AC: 304 AN: 3494

European-Finnish (FIN) AF: 0.123 AC: 801 AN: 6498

Middle Eastern (MID) AF: 0.0440 AC: 8 AN: 182

European-Non Finnish (NFE) AF: 0.0589 AC: 2897 AN: 49180

Other (OTH) AF: 0.0792 AC: 114 AN: 1440

Alfa AF: 0.0438 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (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
PhyloP100		-0.41
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: rs11326739; hg19: chr11-88068256;