rs767122713
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_020533.3(MCOLN1):āc.694A>Cā(p.Thr232Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.000052 ( 0 hom. )
Consequence
MCOLN1
NM_020533.3 missense
NM_020533.3 missense
Scores
5
9
5
Clinical Significance
Conservation
PhyloP100: 4.89
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.923
PP5
Variant 19-7527877-A-C is Pathogenic according to our data. Variant chr19-7527877-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCOLN1 | NM_020533.3 | c.694A>C | p.Thr232Pro | missense_variant | 6/14 | ENST00000264079.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCOLN1 | ENST00000264079.11 | c.694A>C | p.Thr232Pro | missense_variant | 6/14 | 1 | NM_020533.3 | P1 | |
MCOLN1 | ENST00000601003.1 | c.585A>C | p.Ser195= | synonymous_variant | 5/5 | 3 | |||
MCOLN1 | ENST00000394321.9 | n.1009A>C | non_coding_transcript_exon_variant | 5/13 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152080Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251404Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135888
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GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461714Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 42AN XY: 727184
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74288
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucolipidosis type IV Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 14, 2019 | Variant summary: MCOLN1 c.694A>C (p.Thr232Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251404 control chromosomes (gnomAD). The variant, c.694A>C, has been reported in the literature in individuals affected with Mucolipidosis Type 4 (Bargal_2001, Slaugenhaupt_2002, Geer_2010, Chaer_2018). These data indicate that the variant may be associated with disease. One publication, Dong_2008, reports this variant are shown to impair TRPML1s ability to permeate Fe2+ and residual activity is <10% of normal. One submitter has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | Associated with severe phenotype - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 232 of the MCOLN1 protein (p.Thr232Pro). This variant is present in population databases (rs767122713, gnomAD 0.004%). This missense change has been observed in individual(s) with mucolipidosis type IV (PMID: 11317355, 20159435, 30120981). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MCOLN1 protein function. Experimental studies have shown that this missense change affects MCOLN1 function (PMID: 15178326, 18794901, 28112729). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at