11-1763852-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001909.5(CTSD):c.8C>G(p.Pro3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000051 in 1,372,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

CTSD
NM_001909.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.399

Publications

3 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, Genomics England PanelApp, G2P

CTSD links:

ENSG00000250644 (HGNC:):

ENSG00000250644 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07931745).

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.8C>G	p.Pro3Arg	missense	Exon 1 of 9	NP_001900.1	P07339

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTSD	ENST00000236671.7	TSL:1 MANE Select	c.8C>G	p.Pro3Arg	missense	Exon 1 of 9	ENSP00000236671.2	P07339
ENSG00000250644	ENST00000636615.1	TSL:5	c.8C>G	p.Pro3Arg	missense	Exon 1 of 10	ENSP00000490014.1	A0A1B0GU92
ENSG00000250644	ENST00000636397.1	TSL:5	c.8C>G	p.Pro3Arg	missense	Exon 1 of 10	ENSP00000489910.1	A0A1B0GU03

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000166

AC:

AN:

120710

AF XY:

0.0000302

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000510

AC:

AN:

1372514

Hom.:

Cov.:

AF XY:

0.00000886

AC XY:

AN XY:

677288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29074

American (AMR)

AF:

0.00

AC:

AN:

34842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24700

East Asian (EAS)

AF:

0.00

AC:

AN:

33960

South Asian (SAS)

AF:

0.0000902

AC:

AN:

77638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4372

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1073486

Other (OTH)

AF:

0.00

AC:

AN:

57204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.1

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.32

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.43

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-0.40

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.36

REVEL

Benign

0.047

Sift

Benign

0.41

Sift4G

Benign

0.48

Polyphen

0.26

Vest4

0.18

MutPred

0.19

Loss of glycosylation at P3 (P = 0.033)

MVP

0.44

MPC

0.53

ClinPred

0.091

GERP RS

1.3

PromoterAI

-0.077

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.043

gMVP

0.40

Mutation Taster

=97/3

polymorphism

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over