11-1761334-G-A

Position:

• chr11-1761334-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001909.5(CTSD):​c.203C>T​(p.Pro68Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

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]

ENSG00000250644 (HGNC:):

PRADX (HGNC:40168): (PRC2 and DDX5 associated lncRNA)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSD	NM_001909.5	c.203C>T	p.Pro68Leu	missense_variant	2/9	ENST00000236671.7	NP_001900.1
PRADX	NR_182291.1	n.863G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7	c.203C>T	p.Pro68Leu	missense_variant	2/9	1	NM_001909.5	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	c.203C>T	p.Pro68Leu	missense_variant	2/10	5		ENSP00000490014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2019

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with CTSD-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 68 of the CTSD protein (p.Pro68Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;.;D;T;.;T;.;T;.;.;T
Eigen	Benign	0.17
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;T;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.6	.;.;M;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-7.5	.;.;D;.;.;.;.;.;D;D;.
REVEL	Benign	0.27
Sift	Uncertain	0.0010	.;.;D;.;.;.;.;.;D;D;.
Sift4G	Uncertain	0.033	.;.;D;.;.;.;.;.;T;.;.
Polyphen		0.99	.;.;D;.;.;.;.;.;.;.;.
Vest4		0.59
MutPred		0.39		Loss of methylation at K72 (P = 0.0376);Loss of methylation at K72 (P = 0.0376);Loss of methylation at K72 (P = 0.0376);Loss of methylation at K72 (P = 0.0376);Loss of methylation at K72 (P = 0.0376);Loss of methylation at K72 (P = 0.0376);Loss of methylation at K72 (P = 0.0376);Loss of methylation at K72 (P = 0.0376);.;.;.;
MVP		0.74
MPC		0.70
ClinPred		0.99	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs11555044; hg19: chr11-1782564;