rs2230067

Variant names:

• chr11-1759637-G-A
• rs2230067
• NM_001909.5:c.231C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001909.5(CTSD):​c.231C>T​(p.Ala77Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0781 in 1,612,446 control chromosomes in the GnomAD database, including 5,312 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (347 hom., cov: 33)
  • Exomes 𝑓: 0.080 (4965 hom.)
• Consequence: CTSD NM_001909.5 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.358
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 10

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ENSG00000250644 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-1759637-G-A is Benign according to our data. Variant chr11-1759637-G-A is described in ClinVar as Benign. ClinVar VariationId is 128875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.358 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSD	NM_001909.5	c.231C>T	p.Ala77Ala	splice_region_variant, synonymous_variant	Exon 3 of 9	ENST00000236671.7	NP_001900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7	c.231C>T	p.Ala77Ala	splice_region_variant, synonymous_variant	Exon 3 of 9	1	NM_001909.5	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	c.231C>T	p.Ala77Ala	splice_region_variant, synonymous_variant	Exon 3 of 10	5		ENSP00000490014.1

Frequencies

GnomAD3 genomes AF: 0.0628 AC: 9556 AN: 152170 Hom.: 344 Cov.: 33

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0718

Gnomad ASJ AF: 0.0904

Gnomad EAS AF: 0.0287

Gnomad SAS AF: 0.0900

Gnomad FIN AF: 0.0460

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0825

Gnomad OTH AF: 0.0778

GnomAD2 exomes AF: 0.0699 AC: 17415 AN: 249096 AF XY: 0.0737

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.0462

Gnomad ASJ exome AF: 0.0947

Gnomad EAS exome AF: 0.0327

Gnomad FIN exome AF: 0.0526

Gnomad NFE exome AF: 0.0827

Gnomad OTH exome AF: 0.0866

GnomAD4 exome AF: 0.0797 AC: 116303 AN: 1460158 Hom.: 4965 Cov.: 33 AF XY: 0.0802 AC XY: 58281 AN XY: 726278

African (AFR) AF: 0.0290 AC: 970 AN: 33470

American (AMR) AF: 0.0472 AC: 2111 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0881 AC: 2300 AN: 26092

East Asian (EAS) AF: 0.0245 AC: 973 AN: 39676

South Asian (SAS) AF: 0.0951 AC: 8199 AN: 86222

European-Finnish (FIN) AF: 0.0514 AC: 2704 AN: 52608

Middle Eastern (MID) AF: 0.125 AC: 718 AN: 5744

European-Non Finnish (NFE) AF: 0.0841 AC: 93448 AN: 1111330

Other (OTH) AF: 0.0809 AC: 4880 AN: 60330

GnomAD4 genome AF: 0.0628 AC: 9558 AN: 152288 Hom.: 347 Cov.: 33 AF XY: 0.0611 AC XY: 4552 AN XY: 74472

African (AFR) AF: 0.0298 AC: 1238 AN: 41570

American (AMR) AF: 0.0718 AC: 1098 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0904 AC: 314 AN: 3472

East Asian (EAS) AF: 0.0286 AC: 148 AN: 5178

South Asian (SAS) AF: 0.0896 AC: 433 AN: 4832

European-Finnish (FIN) AF: 0.0460 AC: 489 AN: 10620

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0826 AC: 5614 AN: 67992

Other (OTH) AF: 0.0789 AC: 167 AN: 2116

Alfa AF: 0.0708 Hom.: 218

Bravo AF: 0.0618

Asia WGS AF: 0.0820 AC: 285 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

May 26, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Neuronal ceroid lipofuscinosis 10 Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 15, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Mar 14, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2230067; hg19: chr11-1780867;