20-45891598-CCTGCTGCTGCTGCTGCTGCTGCTGCT-CCTGCTGCTGCTGCTGCTGCT

Position:

• chr20-45891598-CCTGCTGCTGCTGCTGCTGCTGCTGCT-CCTGCTGCTGCTGCTGCTGCT

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_000308.4(CTSA):​c.51_56del​(p.Leu18_Leu19del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,506,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: CTSA NM_000308.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.48

Genes affected

CTSA (HGNC:9251): (cathepsin A) This gene encodes a member of the peptidase S10 family of serine carboxypeptidases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate two chains that comprise the heterodimeric active enzyme. This enzyme possesses deamidase, esterase and carboxypeptidase activities and acts as a scaffold in the lysosomal multienzyme complex. Mutations in this gene are associated with galactosialidosis. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 20-45891598-CCTGCTG-C is Benign according to our data. Variant chr20-45891598-CCTGCTG-C is described in ClinVar as [Likely_benign]. Clinvar id is 459631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSA	NM_000308.4	c.51_56del	p.Leu18_Leu19del	inframe_deletion	2/15	ENST00000646241.3
CTSA	NM_001127695.3	c.51_56del	p.Leu18_Leu19del	inframe_deletion	2/15
CTSA	NM_001167594.3	c.51_56del	p.Leu18_Leu19del	inframe_deletion	2/14
CTSA	NR_133656.2	n.96_101del		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSA	ENST00000646241.3	c.51_56del	p.Leu18_Leu19del	inframe_deletion	2/15		NM_000308.4

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149718 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000976

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000417 AC: 85 AN: 203638 Hom.: 0 AF XY: 0.000310 AC XY: 35 AN XY: 112766

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000209

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000205

Gnomad SAS exome AF: 0.0000377

Gnomad FIN exome AF: 0.00218

Gnomad NFE exome AF: 0.000372

Gnomad OTH exome AF: 0.000392

GnomAD4 exome AF: 0.0000737 AC: 100 AN: 1356660 Hom.: 0 AF XY: 0.0000696 AC XY: 47 AN XY: 674970

Gnomad4 AFR exome AF: 0.0000647

Gnomad4 AMR exome AF: 0.0000744

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000381

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.0000376

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 149832 Hom.: 0 Cov.: 0 AF XY: 0.0000137 AC XY: 1 AN XY: 73032

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000976

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 08, 2021	- -

CTSA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72555383; hg19: chr20-44520237;