chr11-1759637-G-A

Variant names:

• chr11-1759637-G-A
• rs2230067
• NM_001909.5:c.231C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001909.5(CTSD):​c.231C>T​(p.Ala77Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0781 in 1,612,446 control chromosomes in the GnomAD database, including 5,312 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (347 hom., cov: 33)
  • Exomes 𝑓: 0.080 (4965 hom.)
• Consequence: CTSD NM_001909.5 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.358
• Publications: 13 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-1759637-G-A is Benign according to our data. Variant chr11-1759637-G-A is described in ClinVar as Benign. ClinVar VariationId is 128875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.358 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0826 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.231C>T	p.Ala77Ala	splice_region synonymous	Exon 3 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.231C>T	p.Ala77Ala	splice_region synonymous	Exon 3 of 9	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.231C>T	p.Ala77Ala	splice_region synonymous	Exon 3 of 10	ENSP00000490014.1	A0A1B0GU92
	ENSG00000250644	ENST00000636397.1	TSL:5	c.231C>T	p.Ala77Ala	splice_region synonymous	Exon 3 of 10	ENSP00000489910.1	A0A1B0GU03

Frequencies

GnomAD3 genomes AF: 0.0628 AC: 9556 AN: 152170 Hom.: 344 Cov.: 33

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0718

Gnomad ASJ AF: 0.0904

Gnomad EAS AF: 0.0287

Gnomad SAS AF: 0.0900

Gnomad FIN AF: 0.0460

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0825

Gnomad OTH AF: 0.0778

GnomAD2 exomes AF: 0.0699 AC: 17415 AN: 249096 AF XY: 0.0737

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.0462

Gnomad ASJ exome AF: 0.0947

Gnomad EAS exome AF: 0.0327

Gnomad FIN exome AF: 0.0526

Gnomad NFE exome AF: 0.0827

Gnomad OTH exome AF: 0.0866

GnomAD4 exome AF: 0.0797 AC: 116303 AN: 1460158 Hom.: 4965 Cov.: 33 AF XY: 0.0802 AC XY: 58281 AN XY: 726278

African (AFR) AF: 0.0290 AC: 970 AN: 33470

American (AMR) AF: 0.0472 AC: 2111 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0881 AC: 2300 AN: 26092

East Asian (EAS) AF: 0.0245 AC: 973 AN: 39676

South Asian (SAS) AF: 0.0951 AC: 8199 AN: 86222

European-Finnish (FIN) AF: 0.0514 AC: 2704 AN: 52608

Middle Eastern (MID) AF: 0.125 AC: 718 AN: 5744

European-Non Finnish (NFE) AF: 0.0841 AC: 93448 AN: 1111330

Other (OTH) AF: 0.0809 AC: 4880 AN: 60330

GnomAD4 genome AF: 0.0628 AC: 9558 AN: 152288 Hom.: 347 Cov.: 33 AF XY: 0.0611 AC XY: 4552 AN XY: 74472

African (AFR) AF: 0.0298 AC: 1238 AN: 41570

American (AMR) AF: 0.0718 AC: 1098 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0904 AC: 314 AN: 3472

East Asian (EAS) AF: 0.0286 AC: 148 AN: 5178

South Asian (SAS) AF: 0.0896 AC: 433 AN: 4832

European-Finnish (FIN) AF: 0.0460 AC: 489 AN: 10620

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0826 AC: 5614 AN: 67992

Other (OTH) AF: 0.0789 AC: 167 AN: 2116

Alfa AF: 0.0708 Hom.: 218

Bravo AF: 0.0618

Asia WGS AF: 0.0820 AC: 285 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Neuronal ceroid lipofuscinosis 10 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	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: rs2230067; hg19: chr11-1780867;