11-1753985-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001909.5(CTSD):​c.972+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CTSD NM_001909.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ENSG00000250644 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-1753985-G-C is Benign according to our data. Variant chr11-1753985-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1621172.Status of the report is criteria_provided_single_submitter, 1 stars.

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.972+9C>G		intron	N/A	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.972+9C>G		intron	N/A	ENSP00000236671.2	P07339
	ENSG00000250644	ENST00000636615.1	TSL:5	c.972+9C>G		intron	N/A	ENSP00000490014.1	A0A1B0GU92
	ENSG00000250644	ENST00000636397.1	TSL:5	c.972+9C>G		intron	N/A	ENSP00000489910.1	A0A1B0GU03

Frequencies

GnomAD3 genomes AF: 0.0000425 AC: 6 AN: 141062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000303

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000262

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000467

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000436 AC: 1 AN: 229376 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000282 AC: 143 AN: 507742 Hom.: 0 Cov.: 25 AF XY: 0.000269 AC XY: 74 AN XY: 275206

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000227 AC: 3 AN: 13208

American (AMR) AF: 0.00 AC: 0 AN: 35990

Ashkenazi Jewish (ASJ) AF: 0.0000787 AC: 1 AN: 12706

East Asian (EAS) AF: 0.000188 AC: 3 AN: 15996

South Asian (SAS) AF: 0.0000436 AC: 3 AN: 68882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3010

European-Non Finnish (NFE) AF: 0.000414 AC: 127 AN: 306948

Other (OTH) AF: 0.000285 AC: 6 AN: 21024

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000425 AC: 6 AN: 141202 Hom.: 0 Cov.: 32 AF XY: 0.0000584 AC XY: 4 AN XY: 68528

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000253 AC: 1 AN: 39572

American (AMR) AF: 0.00 AC: 0 AN: 14400

Ashkenazi Jewish (ASJ) AF: 0.000303 AC: 1 AN: 3302

East Asian (EAS) AF: 0.00 AC: 0 AN: 4040

South Asian (SAS) AF: 0.000260 AC: 1 AN: 3842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000467 AC: 3 AN: 64184

Other (OTH) AF: 0.00 AC: 0 AN: 2010

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.052
DANN	Benign	0.72
PhyloP100		-1.6
PromoterAI		-0.011	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs746243061;

hg19: chr11-1775215;