NM_001909.5:c.566C>T

Variant names:

• chr11-1757462-G-A
• rs1554962634
• NM_001909.5:c.566C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001909.5(CTSD):​c.566C>T​(p.Thr189Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T189T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.04
• 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, Genomics England PanelApp, G2P

ENSG00000250644 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34948856).

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.566C>T	p.Thr189Ile	missense	Exon 5 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.566C>T	p.Thr189Ile	missense	Exon 5 of 9	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.566C>T	p.Thr189Ile	missense	Exon 5 of 10	ENSP00000490014.1	A0A1B0GU92
	ENSG00000250644	ENST00000636397.1	TSL:5	c.566C>T	p.Thr189Ile	missense	Exon 5 of 10	ENSP00000489910.1	A0A1B0GU03

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Neuronal ceroid lipofuscinosis (1)
-	1	-	Neuronal ceroid lipofuscinosis 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.15	T
Polyphen		0.87	P
Vest4		0.39
MutPred		0.50		Gain of methylation at K184 (P = 0.0759)
MVP		0.70
MPC		1.1
ClinPred		0.89	D
GERP RS		1.1
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.76
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1554962634; hg19: chr11-1778692;