rs147278302

Positions:

chr11-1754122-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.0070 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0068 ( 100 hom. )

Consequence

CTSD
NM_001909.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.777

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSD	NM_001909.5 linkuse as main transcript	c.844G>A	p.Gly282Arg	missense_variant	7/9	ENST00000236671.7	NP_001900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7 linkuse as main transcript	c.844G>A	p.Gly282Arg	missense_variant	7/9	1	NM_001909.5	ENSP00000236671	P2

Frequencies

GnomAD3 genomes

AF:

0.00700

AC:

1066

AN:

152196

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0105

AC XY:

1398

AN XY:

133072

show subpopulations

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.:

AF XY:

0.00756

AC XY:

5486

AN XY:

725186

show subpopulations

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.:

Cov.:

AF XY:

0.00838

AC XY:

624

AN XY:

74468

show subpopulations

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.:

Bravo

AF:

0.00365

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00651

AC:

ExAC

AF:

0.00926

AC:

1122

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00664

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2017	- -

Neuronal ceroid lipofuscinosis 10

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 12, 2021	- -
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, 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	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 22, 2016	- -

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. -

Neuronal ceroid lipofuscinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.24

.;.;T;T;.;T;.;T;.;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.12

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

MutationAssessor

Benign

1.1

.;.;L;.;.;.;.;.;.;.

MutationTaster

Benign

0.95

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.76

.;.;N;.;.;.;.;.;N;N

REVEL

Benign

0.033

Sift

Benign

0.23

.;.;T;.;.;.;.;.;T;T

Sift4G

Benign

0.43

.;.;T;.;.;.;.;.;T;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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over