rs147278302

chr11-1754122-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/20 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.777

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 128877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1754122-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSD	NM_001909.5	c.844G>A	p.Gly282Arg	missense_variant	7/9	ENST00000236671.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSD	ENST00000236671.7	c.844G>A	p.Gly282Arg	missense_variant	7/9	1	NM_001909.5	P2

Frequencies

GnomAD3 genomes AF: 0.00700 AC: 1066 AN: 152196 Hom.: 8 Cov.: 33

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

GnomAD3 exomes AF: 0.00959 AC: 2339 AN: 243958 Hom.: 31 AF XY: 0.0105 AC XY: 1398 AN XY: 133072

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 SAS exome AF: 0.0214

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.: 37 AF XY: 0.00756 AC XY: 5486 AN XY: 725186

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0219

Gnomad4 FIN exome AF: 0.0320

Gnomad4 NFE exome AF: 0.00481

Gnomad4 OTH exome AF: 0.00682

GnomAD4 genome AF: 0.00699 AC: 1064 AN: 152314 Hom.: 8 Cov.: 33 AF XY: 0.00838 AC XY: 624 AN XY: 74468

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.0136

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.00659

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00523 Hom.: 3

Bravo AF: 0.00365

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00926 AC: 1122

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00664

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2017	- -

Neuronal ceroid lipofuscinosis 10 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 12, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Sep 22, 2016

- -

Neuronal ceroid lipofuscinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;T;D;D;T;D
MetaRNN	Benign	0.0025	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.33	T
Polyphen		0.011	.;.;B;.;.;.;.;.;.;.
Vest4		0.29
MutPred		0.17		Loss of catalytic residue at G282 (P = 0.0378);Loss of catalytic residue at G282 (P = 0.0378);Loss of catalytic residue at G282 (P = 0.0378);.;Loss of catalytic residue at G282 (P = 0.0378);.;Loss of catalytic residue at G282 (P = 0.0378);.;.;.;
MVP		0.51
MPC		0.64
ClinPred		0.0055	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.49

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: rs147278302; hg19: chr11-1775352;