Genetic Variant NM_000308.4:c.51_56delGCTGCT (chr20-45891598-CCTGCTG-C) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM2BP3BP6_Very_Strong

The NM_000308.4(CTSA):c.51_56delGCTGCT(p.Leu18_Leu19del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.48

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

galactosialidosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Illumina, G2P

CTSA links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_000308.4

BP6

Variant 20-45891598-CCTGCTG-C is Benign according to our data. Variant chr20-45891598-CCTGCTG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 459631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000308.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTSA	NM_000308.4	MANE Select	c.51_56delGCTGCT	p.Leu18_Leu19del	disruptive_inframe_deletion	Exon 2 of 15	NP_000299.3	P10619-1
CTSA	NM_001127695.3		c.51_56delGCTGCT	p.Leu18_Leu19del	disruptive_inframe_deletion	Exon 2 of 15	NP_001121167.1	P10619-1
CTSA	NM_001167594.3		c.51_56delGCTGCT	p.Leu18_Leu19del	disruptive_inframe_deletion	Exon 2 of 14	NP_001161066.2	P10619-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTSA	ENST00000646241.3	MANE Select	c.51_56delGCTGCT	p.Leu18_Leu19del	disruptive_inframe_deletion	Exon 2 of 15	ENSP00000493613.2	P10619-1
CTSA	ENST00000372484.8	TSL:1	c.105_110delGCTGCT	p.Leu36_Leu37del	disruptive_inframe_deletion	Exon 2 of 15	ENSP00000361562.3	X6R8A1
CTSA	ENST00000191018.9	TSL:1	c.51_56delGCTGCT	p.Leu18_Leu19del	disruptive_inframe_deletion	Exon 2 of 15	ENSP00000191018.5	P10619-1

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149718

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000417

AC:

AN:

203638

AF XY:

0.000310

show subpopulations

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 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.:

AF XY:

0.0000696

AC XY:

AN XY:

674970

show subpopulations

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

African (AFR)

AF:

0.0000647

AC:

AN:

30896

American (AMR)

AF:

0.0000744

AC:

AN:

40324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24686

East Asian (EAS)

AF:

0.00

AC:

AN:

37474

South Asian (SAS)

AF:

0.0000381

AC:

AN:

78720

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

44550

Middle Eastern (MID)

AF:

0.000182

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

1038442

Other (OTH)

AF:

0.0000178

AC:

AN:

56078

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.311

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000133

AC:

AN:

149832

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73032

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

40830

American (AMR)

AF:

0.00

AC:

AN:

15000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

4642

South Asian (SAS)

AF:

0.00

AC:

AN:

4696

European-Finnish (FIN)

AF:

0.0000976

AC:

AN:

10244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67686

Other (OTH)

AF:

0.00

AC:

AN:

2078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0241

Hom.:

2124

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined deficiency of sialidase AND beta galactosidase (2)

CTSA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=176/24

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over