20-45891598-CCTGCTGCTGCTGCTGCTGCTGCTGCT-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000308.4(CTSA):c.54_56dupGCT(p.Leu19dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0059 ( 7 hom. )

Consequence

CTSA
NM_000308.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.48

Variant links:

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]

CTSA links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 20-45891598-C-CCTG is Benign according to our data. Variant chr20-45891598-C-CCTG is described in ClinVar as [Likely_benign]. Clinvar id is 632780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00464 (696/149906) while in subpopulation NFE AF= 0.00777 (526/67714). AF 95% confidence interval is 0.00722. There are 1 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSA	NM_000308.4 link	c.54_56dupGCT	p.Leu19dup	disruptive_inframe_insertion	Exon 2 of 15	ENST00000646241.3	NP_000299.3	P10619-1X6R8A1
CTSA	NM_001127695.3 link	c.54_56dupGCT	p.Leu19dup	disruptive_inframe_insertion	Exon 2 of 15		NP_001121167.1	P10619-1
CTSA	NM_001167594.3 link	c.54_56dupGCT	p.Leu19dup	disruptive_inframe_insertion	Exon 2 of 14		NP_001161066.2	P10619-2B4E324X6R5C5
CTSA	NR_133656.2 link	n.99_101dupGCT		non_coding_transcript_exon_variant	Exon 2 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3 link	c.54_56dupGCT	p.Leu19dup	disruptive_inframe_insertion	Exon 2 of 15		NM_000308.4	ENSP00000493613.2		P10619-1

Frequencies

GnomAD3 genomes

AF:

0.00465

AC:

696

AN:

149792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000884

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00107

Gnomad SAS

AF:

0.00106

Gnomad FIN

AF:

0.00214

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00777

Gnomad OTH

AF:

0.00291

GnomAD3 exomes

AF:

0.00573

AC:

1167

AN:

203638

Hom.:

AF XY:

0.00565

AC XY:

637

AN XY:

112766

show subpopulations

Gnomad AFR exome

AF:

0.00134

Gnomad AMR exome

AF:

0.00328

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.000683

Gnomad SAS exome

AF:

0.00151

Gnomad FIN exome

AF:

0.00249

Gnomad NFE exome

AF:

0.00908

Gnomad OTH exome

AF:

0.00529

GnomAD4 exome

AF:

0.00585

AC:

8382

AN:

1432024

Hom.:

Cov.:

AF XY:

0.00571

AC XY:

4068

AN XY:

712836

show subpopulations

Gnomad4 AFR exome

AF:

0.000882

Gnomad4 AMR exome

AF:

0.00248

Gnomad4 ASJ exome

AF:

0.0110

Gnomad4 EAS exome

AF:

0.000715

Gnomad4 SAS exome

AF:

0.00123

Gnomad4 FIN exome

AF:

0.00226

Gnomad4 NFE exome

AF:

0.00675

Gnomad4 OTH exome

AF:

0.00545

GnomAD4 genome

AF:

0.00464

AC:

696

AN:

149906

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

303

AN XY:

73070

show subpopulations

Gnomad4 AFR

AF:

0.000881

Gnomad4 AMR

AF:

0.00380

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.00108

Gnomad4 SAS

AF:

0.00106

Gnomad4 FIN

AF:

0.00214

Gnomad4 NFE

AF:

0.00777

Gnomad4 OTH

AF:

0.00288

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 15, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CTSA c.108_110dupGCT (p.Leu37dup) results in an in-frame insertion of a leucine into a repetitive region of the encoded protein sequence; this region consists of several consecutive leucines and doesn't have a known function. The variant allele was found at a frequency of 0.0055 in 230752 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 3.46 fold of the estimated maximal expected allele frequency for a pathogenic variant in CTSA causing Galactosialidosis phenotype (0.0016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.108_110dupGCT in individuals affected with Galactosialidosis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

CTSA-related disorder

Benign:1

Apr 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided

Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CTSA: BS2 -

Combined deficiency of sialidase AND beta galactosidase

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over