rs2230067

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 128875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1759637-G-A is described in Lovd as [Benign].
• 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

GnomAD3 exomes AF: 0.0699 AC: 17415 AN: 249096 Hom.: 689 AF XY: 0.0737 AC XY: 9949 AN XY: 135038

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 SAS exome AF: 0.0949

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

Gnomad4 AFR exome AF: 0.0290

Gnomad4 AMR exome AF: 0.0472

Gnomad4 ASJ exome AF: 0.0881

Gnomad4 EAS exome AF: 0.0245

Gnomad4 SAS exome AF: 0.0951

Gnomad4 FIN exome AF: 0.0514

Gnomad4 NFE exome AF: 0.0841

Gnomad4 OTH exome AF: 0.0809

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

Gnomad4 AFR AF: 0.0298

Gnomad4 AMR AF: 0.0718

Gnomad4 ASJ AF: 0.0904

Gnomad4 EAS AF: 0.0286

Gnomad4 SAS AF: 0.0896

Gnomad4 FIN AF: 0.0460

Gnomad4 NFE AF: 0.0826

Gnomad4 OTH AF: 0.0789

Alfa AF: 0.0712 Hom.: 209

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

-

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

Sep 15, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2230067; hg19: chr11-1780867;