rs147278302

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001909.5(CTSD):c.844G>A(p.Gly282Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,609,774 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G282V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0070 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0068 ( 100 hom. )

Consequence

CTSD
NM_001909.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.777

Publications

13 publications found

Variant links:

Genes affected

CTSD (HGNC:2529): (cathepsin D) This gene encodes a member of the A1 family of peptidases. The encoded preproprotein is proteolytically processed to generate multiple protein products. These products include the cathepsin D light and heavy chains, which heterodimerize to form the mature enzyme. This enzyme exhibits pepsin-like activity and plays a role in protein turnover and in the proteolytic activation of hormones and growth factors. Mutations in this gene play a causal role in neuronal ceroid lipofuscinosis-10 and may be involved in the pathogenesis of several other diseases, including breast cancer and possibly Alzheimer's disease. [provided by RefSeq, Nov 2015]

CTSD Gene-Disease associations (from GenCC):

neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 10
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

CTSD links:

ENSG00000250644 (HGNC:):

ENSG00000250644 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025467277).

BP6

Variant 11-1754122-C-T is Benign according to our data. Variant chr11-1754122-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00699 (1064/152314) while in subpopulation SAS AF = 0.0209 (101/4830). AF 95% confidence interval is 0.0176. There are 8 homozygotes in GnomAd4. There are 624 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001909.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSD	NM_001909.5	MANE Select	c.844G>A	p.Gly282Arg	missense	Exon 7 of 9	NP_001900.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CTSD	ENST00000236671.7	TSL:1 MANE Select	c.844G>A	p.Gly282Arg	missense	Exon 7 of 9	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	TSL:5	c.844G>A	p.Gly282Arg	missense	Exon 7 of 10	ENSP00000490014.1
ENSG00000250644	ENST00000636397.1	TSL:5	c.844G>A	p.Gly282Arg	missense	Exon 7 of 10	ENSP00000489910.1

Frequencies

GnomAD3 genomes

AF:

0.00700

AC:

1066

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.0136

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0211

Gnomad FIN

AF:

0.0360

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00659

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00959

AC:

2339

AN:

243958

AF XY:

0.0105

show subpopulations

Gnomad AFR exome

AF:

0.000697

Gnomad AMR exome

AF:

0.00245

Gnomad ASJ exome

AF:

0.0116

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.0362

Gnomad NFE exome

AF:

0.00685

Gnomad OTH exome

AF:

0.00854

GnomAD4 exome

AF:

0.00677

AC:

9861

AN:

1457460

Hom.:

100

Cov.:

AF XY:

0.00756

AC XY:

5486

AN XY:

725186

show subpopulations

African (AFR)

AF:

0.000628

AC:

AN:

33464

American (AMR)

AF:

0.00275

AC:

123

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

353

AN:

26098

East Asian (EAS)

AF:

0.000101

AC:

AN:

39668

South Asian (SAS)

AF:

0.0219

AC:

1886

AN:

86172

European-Finnish (FIN)

AF:

0.0320

AC:

1587

AN:

49668

Middle Eastern (MID)

AF:

0.0229

AC:

132

AN:

5754

European-Non Finnish (NFE)

AF:

0.00481

AC:

5344

AN:

1111676

Other (OTH)

AF:

0.00682

AC:

411

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

615

1230

1846

2461

3076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

376

564

752

940

<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:

0.00699

AC:

1064

AN:

152314

Hom.:

Cov.:

AF XY:

0.00838

AC XY:

624

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41570

American (AMR)

AF:

0.00222

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.0209

AC:

101

AN:

4830

European-Finnish (FIN)

AF:

0.0360

AC:

383

AN:

10628

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00659

AC:

448

AN:

68022

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00513

Hom.:

Bravo

AF:

0.00365

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00651

AC:

ExAC

AF:

0.00926

AC:

1122

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00664

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuronal ceroid lipofuscinosis 10 (4)

not specified (4)

not provided (2)

Inborn genetic diseases (1)

Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.24

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

0.78

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.76

REVEL

Benign

0.033

Sift

Benign

0.23

Sift4G

Benign

0.43

Polyphen

0.011

Vest4

0.29

MutPred

0.17

Loss of catalytic residue at G282 (P = 0.0378)

MVP

0.51

MPC

0.64

ClinPred

0.0055

GERP RS

2.1

PromoterAI

0.023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.49

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over