11-1763796-C-T

Variant names:

• chr11-1763796-C-T
• rs1060502503
• NM_001909.5:c.64G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001909.5(CTSD):​c.64G>A​(p.Val22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000655 in 1,373,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07987222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSD	NM_001909.5	c.64G>A	p.Val22Ile	missense_variant	Exon 1 of 9	ENST00000236671.7	NP_001900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSD	ENST00000236671.7	c.64G>A	p.Val22Ile	missense_variant	Exon 1 of 9	1	NM_001909.5	ENSP00000236671.2
ENSG00000250644	ENST00000636615.1	c.64G>A	p.Val22Ile	missense_variant	Exon 1 of 10	5		ENSP00000490014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000822 AC: 1 AN: 121718 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000219

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000655 AC: 9 AN: 1373350 Hom.: 0 Cov.: 30 AF XY: 0.00000738 AC XY: 5 AN XY: 677848

African (AFR) AF: 0.00 AC: 0 AN: 29454

American (AMR) AF: 0.00 AC: 0 AN: 35078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24784

East Asian (EAS) AF: 0.00 AC: 0 AN: 34280

South Asian (SAS) AF: 0.00 AC: 0 AN: 77990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4138

European-Non Finnish (NFE) AF: 0.00000837 AC: 9 AN: 1074748

Other (OTH) AF: 0.00 AC: 0 AN: 57280

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.016
DANN	Benign	0.84
DEOGEN2	Benign	0.28	.;.;T;T;.;T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.60	T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.080	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.18	.;.;N;.;.;.;.;.
PhyloP100		-2.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.060	.;.;N;.;.;.;.;.
REVEL	Benign	0.068
Sift	Benign	0.86	.;.;T;.;.;.;.;.
Sift4G	Benign	0.64	.;.;T;.;.;.;.;.
Polyphen		0.0020	.;.;B;.;.;.;.;.
Vest4		0.077
MutPred		0.59		Loss of MoRF binding (P = 0.1183);Loss of MoRF binding (P = 0.1183);Loss of MoRF binding (P = 0.1183);Loss of MoRF binding (P = 0.1183);Loss of MoRF binding (P = 0.1183);Loss of MoRF binding (P = 0.1183);Loss of MoRF binding (P = 0.1183);Loss of MoRF binding (P = 0.1183);
MVP		0.055
MPC		0.41
ClinPred		0.067	T
GERP RS		-5.5
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.012
gMVP		0.31
Mutation Taster		=86/14	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: rs1060502503; hg19: chr11-1785026;