22-50084767-AG-AGG
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015166.4(MLC1):c.135dupC(p.Cys46LeufsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_015166.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLC1 | NM_015166.4 | c.135dupC | p.Cys46LeufsTer34 | frameshift_variant | Exon 2 of 12 | ENST00000311597.10 | NP_055981.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLC1 | ENST00000311597.10 | c.135dupC | p.Cys46LeufsTer34 | frameshift_variant | Exon 2 of 12 | 1 | NM_015166.4 | ENSP00000310375.6 | ||
MLC1 | ENST00000395876.6 | c.135dupC | p.Cys46LeufsTer34 | frameshift_variant | Exon 2 of 12 | 1 | ENSP00000379216.2 | |||
MLC1 | ENST00000442311.1 | c.135dupC | p.Cys46LeufsTer105 | frameshift_variant | Exon 2 of 8 | 5 | ENSP00000401385.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 250390Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135472
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461758Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727180
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:7Other:1
NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is classified as pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 15037685, 14572144, 22006981, 12189496 and 11935341. Classification of NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
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A Homozygote Frameshift variant c.135dupC in Exon 2 of the MLC1 gene that results in the amino acid substitution p.Cys46fs*34 was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and and novel in 1KG, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease- causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 4722]. The observed variation has been previously reported in individuals with megalencephalic leukoencephalopathy (Shukla P, et.al., 2011). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:2
The c.135dupC variant in the MLC1 gene has been reported in the homozygous state in several unrelated patients with MLC (Leegwater et al., 2002; Ben-Zeev et al., 2002; Ridder et al., 2011; Saini et al., 2015). The c.135dupC variant causes a frameshift starting with codon Cysteine 46, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 34 of the new reading frame, denoted p.Cys46LeufsX34. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.135dupC variant is observed in 7/245210 (0.003%) alleles in large population cohorts We interpret c.135dupC as a pathogenic variant. -
This sequence change creates a premature translational stop signal (p.Cys46Leufs*34) 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 (rs80358241, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with megalencephalic leukoencephalopathy (PMID: 11935341, 12189496, 21555057). ClinVar contains an entry for this variant (Variation ID: 4722). For these reasons, this variant has been classified as Pathogenic. -
Megalencephalic leukoencephalopathy with subcortical cysts Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at