rs199970387

Variant names:

• chr11-1753290-GGA-G
• rs199970387
• NM_001909.5:c.*211_*212delTC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001909.5(CTSD):​c.*211_*212delTC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 633,750 control chromosomes in the GnomAD database, including 87 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 33)
  • Exomes 𝑓: 0.013 (69 hom.)
• Consequence: CTSD NM_001909.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.846
• Publications: 1 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, Genomics England PanelApp, G2P

ENSG00000250644 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 11-1753290-GGA-G is Benign according to our data. Variant chr11-1753290-GGA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1200404.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0116 (1765/152310) while in subpopulation NFE AF = 0.0156 (1060/68014). AF 95% confidence interval is 0.0148. There are 18 homozygotes in GnomAd4. There are 874 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001909.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSD	NM_001909.5	MANE Select	c.*211_*212delTC		3_prime_UTR	Exon 9 of 9	NP_001900.1	P07339

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSD	ENST00000236671.7	TSL:1 MANE Select	c.*211_*212delTC		3_prime_UTR	Exon 9 of 9	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.1071+511_1071+512delTC		intron	N/A	ENSP00000490014.1	A0A1B0GU92
	CTSD	ENST00000962446.1		c.*211_*212delTC		3_prime_UTR	Exon 10 of 10	ENSP00000632505.1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1766 AN: 152192 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0317

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.0162

GnomAD4 exome AF: 0.0131 AC: 6308 AN: 481440 Hom.: 69 AF XY: 0.0126 AC XY: 3232 AN XY: 256268

African (AFR) AF: 0.00214 AC: 29 AN: 13574

American (AMR) AF: 0.00832 AC: 220 AN: 26446

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 243 AN: 15256

East Asian (EAS) AF: 0.0000322 AC: 1 AN: 31096

South Asian (SAS) AF: 0.00183 AC: 93 AN: 50820

European-Finnish (FIN) AF: 0.0312 AC: 934 AN: 29934

Middle Eastern (MID) AF: 0.0144 AC: 30 AN: 2088

European-Non Finnish (NFE) AF: 0.0154 AC: 4378 AN: 284978

Other (OTH) AF: 0.0139 AC: 380 AN: 27248

GnomAD4 genome AF: 0.0116 AC: 1765 AN: 152310 Hom.: 18 Cov.: 33 AF XY: 0.0117 AC XY: 874 AN XY: 74468

African (AFR) AF: 0.00212 AC: 88 AN: 41564

American (AMR) AF: 0.0107 AC: 164 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.0317 AC: 337 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0156 AC: 1060 AN: 68014

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.0157 Hom.: 2

Bravo AF: 0.00934

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism

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: rs199970387; hg19: chr11-1774520; COSMIC: COSV52586952; COSMIC: COSV52586952;