chr11-1761332-C-T

Position:

• chr11-1761332-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001909.5(CTSD):​c.205G>A​(p.Glu69Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSD	NM_001909.5	c.205G>A	p.Glu69Lys	missense_variant	2/9	ENST00000236671.7	NP_001900.1
PRADX	NR_182291.1	n.861C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7	c.205G>A	p.Glu69Lys	missense_variant	2/9	1	NM_001909.5	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	c.205G>A	p.Glu69Lys	missense_variant	2/10	5		ENSP00000490014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251020 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS 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: 0.00000547 AC: 8 AN: 1461518 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 06, 2024

Variant summary: CTSD c.205G>A (p.Glu69Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251020 control chromosomes. c.205G>A has been reported in the literature in a homozygous individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and the patient had defective enzymatic CTSD activity in dried blood spot detected by mass spectrometry (MS)-based assay (example: Doccini_2016) . These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27072142). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.80	.;.;D;T;.;T;.;T;.;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;T;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.7	.;.;H;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.4	.;.;D;.;.;.;.;.;D;D;.
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	.;.;D;.;.;.;.;.;D;D;.
Sift4G	Uncertain	0.0030	.;.;D;.;.;.;.;.;D;.;.
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.;.
Vest4		0.75
MutPred		0.56		Gain of methylation at E69 (P = 0.0037);Gain of methylation at E69 (P = 0.0037);Gain of methylation at E69 (P = 0.0037);Gain of methylation at E69 (P = 0.0037);Gain of methylation at E69 (P = 0.0037);Gain of methylation at E69 (P = 0.0037);Gain of methylation at E69 (P = 0.0037);Gain of methylation at E69 (P = 0.0037);.;.;.;
MVP		0.66
MPC		1.5
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs895654125; hg19: chr11-1782562; COSMIC: COSV105863218; COSMIC: COSV105863218;