11-1752906-T-G

Variant names:

• chr11-1752906-T-G
• rs8839
• NM_001909.5:c.*597A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001909.5(CTSD):​c.*597A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 164,580 control chromosomes in the GnomAD database, including 2,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1872 hom., cov: 33)
  • Exomes 𝑓: 0.13 (153 hom.)
• Consequence: CTSD NM_001909.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.29
• Publications: 14 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ENSG00000250644 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 11-1752906-T-G is Benign according to our data. Variant chr11-1752906-T-G is described in ClinVar as Benign. ClinVar VariationId is 303822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

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.*597A>C		3_prime_UTR	Exon 9 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.*597A>C		3_prime_UTR	Exon 9 of 9	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.1071+897A>C		intron	N/A	ENSP00000490014.1	A0A1B0GU92
	CTSD	ENST00000962446.1		c.*597A>C		3_prime_UTR	Exon 10 of 10	ENSP00000632505.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23012 AN: 152150 Hom.: 1868 Cov.: 33

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.130 AC: 1598 AN: 12312 Hom.: 153 Cov.: 0 AF XY: 0.139 AC XY: 895 AN XY: 6430

African (AFR) AF: 0.125 AC: 18 AN: 144

American (AMR) AF: 0.0818 AC: 141 AN: 1724

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 22 AN: 120

East Asian (EAS) AF: 0.0619 AC: 26 AN: 420

South Asian (SAS) AF: 0.233 AC: 374 AN: 1606

European-Finnish (FIN) AF: 0.0599 AC: 17 AN: 284

Middle Eastern (MID) AF: 0.214 AC: 30 AN: 140

European-Non Finnish (NFE) AF: 0.122 AC: 891 AN: 7282

Other (OTH) AF: 0.133 AC: 79 AN: 592

GnomAD4 genome AF: 0.151 AC: 23031 AN: 152268 Hom.: 1872 Cov.: 33 AF XY: 0.150 AC XY: 11165 AN XY: 74470

African (AFR) AF: 0.132 AC: 5469 AN: 41564

American (AMR) AF: 0.129 AC: 1971 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 970 AN: 3466

East Asian (EAS) AF: 0.100 AC: 520 AN: 5176

South Asian (SAS) AF: 0.277 AC: 1337 AN: 4822

European-Finnish (FIN) AF: 0.107 AC: 1131 AN: 10614

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11075 AN: 68004

Other (OTH) AF: 0.175 AC: 369 AN: 2112

Alfa AF: 0.154 Hom.: 316

Bravo AF: 0.151

Asia WGS AF: 0.180 AC: 626 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Neuronal ceroid lipofuscinosis 10 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.61
DANN	Benign	0.39
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs8839; hg19: chr11-1774136;