rs1057516766
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015166.4(MLC1):βc.136delβ(p.Cys46AlafsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.0000041 ( 0 hom. )
Consequence
MLC1
NM_015166.4 frameshift
NM_015166.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.13
Genes affected
MLC1 (HGNC:17082): (modulator of VRAC current 1) The function of this gene product is unknown; however, homology to other proteins suggests that it may be an integral membrane transporter. Mutations in this gene have been associated with megalencephalic leukoencephalopathy with subcortical cysts, an autosomal recessive neurological disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 22-50084766-CA-C is Pathogenic according to our data. Variant chr22-50084766-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLC1 | NM_015166.4 | c.136del | p.Cys46AlafsTer12 | frameshift_variant | 2/12 | ENST00000311597.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLC1 | ENST00000311597.10 | c.136del | p.Cys46AlafsTer12 | frameshift_variant | 2/12 | 1 | NM_015166.4 | P1 | |
MLC1 | ENST00000395876.6 | c.136del | p.Cys46AlafsTer12 | frameshift_variant | 2/12 | 1 | P1 | ||
MLC1 | ENST00000442311.1 | c.136del | p.Cys46AlafsTer12 | frameshift_variant | 2/8 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461770Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727198
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jul 04, 2022 | ACMG classification criteria: PVS1 very strong, PS4 moderated, PM2 moderated, PM3 supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 13, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change creates a premature translational stop signal (p.Cys46Alafs*12) in the MLC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLC1 are known to be pathogenic (PMID: 11254442, 16470554, 24824219). This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 19168821). ClinVar contains an entry for this variant (Variation ID: 370785). For these reasons, this variant has been classified as Pathogenic. - |
Megalencephalic leukoencephalopathy with subcortical cysts Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 29, 2020 | - - |
Computational scores
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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