19-7522757-GC-G

Variant names:

• chr19-7522757-GC-G
• NM_020533.3:c.11delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_020533.3(MCOLN1):​c.11delC​(p.Pro4ArgfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MCOLN1 NM_020533.3 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.250
• Publications: 0 publications found

Genes affected

MCOLN1 (HGNC:13356): (mucolipin TRP cation channel 1) This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV. [provided by RefSeq, Oct 2009]

MCOLN1 Gene-Disease associations (from GenCC):

• mucolipidosis type IV

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Lisch epithelial corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000305089 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 89 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-7522757-GC-G is Pathogenic according to our data. Variant chr19-7522757-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4057590.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCOLN1	NM_020533.3	c.11delC	p.Pro4ArgfsTer13	frameshift_variant	Exon 1 of 14	ENST00000264079.11	NP_065394.1
LOC105372261	XR_936293.3	n.936+84delG		intron_variant	Intron 2 of 2
LOC105372261	XR_936294.3	n.936+84delG		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCOLN1	ENST00000264079.11	c.11delC	p.Pro4ArgfsTer13	frameshift_variant	Exon 1 of 14	1	NM_020533.3	ENSP00000264079.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1277096 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 624460

African (AFR) AF: 0.00 AC: 0 AN: 25978

American (AMR) AF: 0.00 AC: 0 AN: 22124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21412

East Asian (EAS) AF: 0.00 AC: 0 AN: 28234

South Asian (SAS) AF: 0.00 AC: 0 AN: 65220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3842

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1026784

Other (OTH) AF: 0.00 AC: 0 AN: 53050

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mucolipidosis type IV Pathogenic:1

Jan 13, 2025

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25

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

hg19: chr19-7587643;