rs768736321
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_020533.3(MCOLN1):c.681-19A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000368 in 1,602,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
MCOLN1
NM_020533.3 intron
NM_020533.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.438
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-7527845-A-C is Pathogenic according to our data. Variant chr19-7527845-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557604.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr19-7527845-A-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCOLN1 | NM_020533.3 | c.681-19A>C | intron_variant | ENST00000264079.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCOLN1 | ENST00000264079.11 | c.681-19A>C | intron_variant | 1 | NM_020533.3 | P1 | |||
MCOLN1 | ENST00000601003.1 | c.572-19A>C | intron_variant | 3 | |||||
MCOLN1 | ENST00000394321.9 | n.977A>C | non_coding_transcript_exon_variant | 5/13 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151922Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251216Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135816
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GnomAD4 exome AF: 0.0000400 AC: 58AN: 1450232Hom.: 0 Cov.: 31 AF XY: 0.0000429 AC XY: 31AN XY: 722378
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151922Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74182
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Mucolipidosis type IV Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 02, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change falls in intron 5 of the MCOLN1 gene. It does not directly change the encoded amino acid sequence of the MCOLN1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs768736321, gnomAD 0.007%). This variant has been observed in individual(s) with MCOLN1-related conditions (PMID: 28604674). 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: 557604). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in intron retention and introduces a premature termination codon (PMID: 28604674). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
La Branchor
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 7
Find out detailed SpliceAI scores and Pangolin per-transcript scores at