rs730882208

Variant names:

• chr11-1753572-G-GATGAAGACGTCGCCC
• rs730882208
• NM_001909.5:c.1155_1169dupGGGCGACGTCTTCAT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4 PP5

The NM_001909.5(CTSD):​c.1155_1169dupGGGCGACGTCTTCAT​(p.Phe389_Ile390insMetGlyAspValPhe) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. I390I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTSD NM_001909.5 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.95
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001909.5.
• PP5: Variant 11-1753572-G-GATGAAGACGTCGCCC is Pathogenic according to our data. Variant chr11-1753572-G-GATGAAGACGTCGCCC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183293.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSD	NM_001909.5	MANE Select	c.1155_1169dupGGGCGACGTCTTCAT	p.Phe389_Ile390insMetGlyAspValPhe	disruptive_inframe_insertion	Exon 9 of 9	NP_001900.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSD	ENST00000236671.7	TSL:1 MANE Select	c.1155_1169dupGGGCGACGTCTTCAT	p.Phe389_Ile390insMetGlyAspValPhe	disruptive_inframe_insertion	Exon 9 of 9	ENSP00000236671.2
	ENSG00000250644	ENST00000636615.1	TSL:5	c.1071+216_1071+230dupGGGCGACGTCTTCAT		intron	N/A	ENSP00000490014.1
	CTSD	ENST00000438213.6	TSL:2	c.1272_1286dupGGGCGACGTCTTCAT	p.Phe428_Ile429insMetGlyAspValPhe	disruptive_inframe_insertion	Exon 9 of 9	ENSP00000415036.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Exaggerated startle response;CN228309:Severe microlissencephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=57/43	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs730882208; hg19: chr11-1774802;