rs797045138

Positions:

• chr11-1753546-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001909.5(CTSD):​c.1196G>A​(p.Arg399His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,786 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: 0.0000021 (0 hom.)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.42

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSD	NM_001909.5	c.1196G>A	p.Arg399His	missense_variant	9/9	ENST00000236671.7	NP_001900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7	c.1196G>A	p.Arg399His	missense_variant	9/9	1	NM_001909.5	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	c.1071+257G>A		intron_variant		5		ENSP00000490014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250532 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135788

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460786 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 11, 2014

- -

Neuronal ceroid lipofuscinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 03, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 399 of the CTSD protein (p.Arg399His). This variant is present in population databases (rs797045138, gnomAD 0.0009%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 25298308). ClinVar contains an entry for this variant (Variation ID: 208849). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D;T;.;T;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D;.;.;.;.;.;D
REVEL	Pathogenic	0.82
Sift	Benign	0.31	T;.;.;.;.;.;T
Sift4G	Benign	0.24	T;.;.;.;.;.;T
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.67
MutPred		0.74		Gain of catalytic residue at R399 (P = 0.1049);.;.;.;.;.;.;
MVP		0.83
MPC		1.6
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs797045138; hg19: chr11-1774776;