chr11-1759562-G-T

Variant names:

• chr11-1759562-G-T
• rs1258957118
• NM_001909.5:c.306C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001909.5(CTSD):​c.306C>A​(p.Asn102Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. N102H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

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.306C>A	p.Asn102Lys	missense	Exon 3 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.306C>A	p.Asn102Lys	missense	Exon 3 of 9	ENSP00000236671.2
	ENSG00000250644	ENST00000636615.1	TSL:5	c.306C>A	p.Asn102Lys	missense	Exon 3 of 10	ENSP00000490014.1
	ENSG00000250644	ENST00000636397.1	TSL:5	c.306C>A	p.Asn102Lys	missense	Exon 3 of 10	ENSP00000489910.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461196 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726924

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: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52808

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		1.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.89		Gain of methylation at N102 (P = 0.031)
MVP		0.71
MPC		1.5
ClinPred		1.0	D
GERP RS		1.2
Varity_R		0.96
gMVP		0.87
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1258957118; hg19: chr11-1780792; COSMIC: COSV52589741; COSMIC: COSV52589741;