rs78306946

Variant names:

• chr11-1754015-G-A
• rs78306946
• NM_001909.5:c.951C>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.951C>T​(p.Ala317Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,479,412 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (103 hom.)
• Consequence: CTSD NM_001909.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.01

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=-0.8).
• BP6: Variant 11-1754015-G-A is Benign according to our data. Variant chr11-1754015-G-A is described in ClinVar as [Benign]. Clinvar id is 137041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSD	NM_001909.5	c.951C>T	p.Ala317Ala	synonymous_variant	Exon 7 of 9	ENST00000236671.7	NP_001900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7	c.951C>T	p.Ala317Ala	synonymous_variant	Exon 7 of 9	1	NM_001909.5	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	c.951C>T	p.Ala317Ala	synonymous_variant	Exon 7 of 10	5		ENSP00000490014.1

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 444 AN: 145918 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0000745

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000816

Gnomad ASJ AF: 0.000293

Gnomad EAS AF: 0.0881

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00292

GnomAD3 exomes AF: 0.00595 AC: 1408 AN: 236662 Hom.: 49 AF XY: 0.00553 AC XY: 714 AN XY: 129088

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.0000596

Gnomad ASJ exome AF: 0.000308

Gnomad EAS exome AF: 0.0737

Gnomad SAS exome AF: 0.000871

Gnomad FIN exome AF: 0.00204

Gnomad NFE exome AF: 0.000236

Gnomad OTH exome AF: 0.00206

GnomAD4 exome AF: 0.00242 AC: 3225 AN: 1333346 Hom.: 103 Cov.: 39 AF XY: 0.00235 AC XY: 1557 AN XY: 662400

Gnomad4 AFR exome AF: 0.0000677

Gnomad4 AMR exome AF: 0.0000497

Gnomad4 ASJ exome AF: 0.000236

Gnomad4 EAS exome AF: 0.0863

Gnomad4 SAS exome AF: 0.000922

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00448

GnomAD4 genome AF: 0.00303 AC: 442 AN: 146066 Hom.: 17 Cov.: 32 AF XY: 0.00344 AC XY: 245 AN XY: 71268

Gnomad4 AFR AF: 0.0000743

Gnomad4 AMR AF: 0.000815

Gnomad4 ASJ AF: 0.000293

Gnomad4 EAS AF: 0.0879

Gnomad4 SAS AF: 0.000986

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.000151

Gnomad4 OTH AF: 0.00289

Alfa AF: 0.000508 Hom.: 0

Bravo AF: 0.00256

Asia WGS AF: 0.0260 AC: 91 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 16, 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. -

Mar 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis 10 Benign:1

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. -

Inborn genetic diseases Benign:1

Feb 01, 2017

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

Jan 30, 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	-0.80
CADD	Benign	0.084
DANN	Benign	0.79
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: rs78306946; hg19: chr11-1775245; COSMIC: COSV52589216; COSMIC: COSV52589216;