chr11-1753985-G-A

Variant names:

• chr11-1753985-G-A
• rs746243061
• NM_001909.5:c.972+9C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001909.5(CTSD):​c.972+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 651,494 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CTSD NM_001909.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.61
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-1753985-G-A is Benign according to our data. Variant chr11-1753985-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 527761.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000125 (64/510412) while in subpopulation NFE AF = 0.000184 (57/309208). AF 95% confidence interval is 0.000146. There are 0 homozygotes in GnomAdExome4. There are 27 alleles in the male GnomAdExome4 subpopulation. Median coverage is 25. This position passed quality control check.

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.972+9C>T		intron	N/A	NP_001900.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSD	ENST00000236671.7	TSL:1 MANE Select	c.972+9C>T		intron	N/A	ENSP00000236671.2
	ENSG00000250644	ENST00000636615.1	TSL:5	c.972+9C>T		intron	N/A	ENSP00000490014.1
	CTSD	ENST00000497544.3	TSL:2	n.597C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0000354 AC: 5 AN: 141082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000779

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000174 AC: 4 AN: 229376 AF XY: 0.00000796

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: 0.0000395

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000125 AC: 64 AN: 510412 Hom.: 0 Cov.: 25 AF XY: 0.0000977 AC XY: 27 AN XY: 276486

African (AFR) AF: 0.00 AC: 0 AN: 13256

American (AMR) AF: 0.0000278 AC: 1 AN: 36010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12738

East Asian (EAS) AF: 0.0000623 AC: 1 AN: 16052

South Asian (SAS) AF: 0.0000145 AC: 1 AN: 68948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3022

European-Non Finnish (NFE) AF: 0.000184 AC: 57 AN: 309208

Other (OTH) AF: 0.000189 AC: 4 AN: 21134

GnomAD4 genome AF: 0.0000354 AC: 5 AN: 141082 Hom.: 0 Cov.: 32 AF XY: 0.0000146 AC XY: 1 AN XY: 68418

African (AFR) AF: 0.00 AC: 0 AN: 39484

American (AMR) AF: 0.00 AC: 0 AN: 14378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3302

East Asian (EAS) AF: 0.00 AC: 0 AN: 4042

South Asian (SAS) AF: 0.00 AC: 0 AN: 3824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000779 AC: 5 AN: 64188

Other (OTH) AF: 0.00 AC: 0 AN: 1988

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

May 22, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neuronal ceroid lipofuscinosis Benign:1

Nov 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.13
DANN	Benign	0.81
PhyloP100		-1.6
PromoterAI		0.0080	Neutral
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: rs746243061; hg19: chr11-1775215;