NM_015166.4:c.136delT
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_015166.4(MLC1):c.136delT(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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
MLC1
NM_015166.4 frameshift
NM_015166.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.13
Publications
2 publications found
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]
MLC1 Gene-Disease associations (from GenCC):
- megalencephalic leukoencephalopathy with subcortical cysts 1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P, Ambry Genetics
- megalencephalic leukoencephalopathy with subcortical cystsInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 22-50084766-CA-C is Pathogenic according to our data. Variant chr22-50084766-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 370785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_015166.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MLC1 | NM_015166.4 | MANE Select | c.136delT | p.Cys46AlafsTer12 | frameshift | Exon 2 of 12 | NP_055981.1 | Q15049-1 | |
| MLC1 | NM_001376472.1 | c.136delT | p.Cys46AlafsTer12 | frameshift | Exon 1 of 11 | NP_001363401.1 | Q15049-1 | ||
| MLC1 | NM_001376473.1 | c.136delT | p.Cys46AlafsTer12 | frameshift | Exon 3 of 13 | NP_001363402.1 | Q15049-1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MLC1 | ENST00000311597.10 | TSL:1 MANE Select | c.136delT | p.Cys46AlafsTer12 | frameshift | Exon 2 of 12 | ENSP00000310375.6 | Q15049-1 | |
| MLC1 | ENST00000395876.6 | TSL:1 | c.136delT | p.Cys46AlafsTer12 | frameshift | Exon 2 of 12 | ENSP00000379216.2 | Q15049-1 | |
| MLC1 | ENST00000879262.1 | c.136delT | p.Cys46AlafsTer12 | frameshift | Exon 3 of 13 | ENSP00000549321.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152222
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
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Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461770Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727198 show subpopulations
GnomAD4 exome
AF:
AC:
6
AN:
1461770
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
727198
show subpopulations
African (AFR)
AF:
AC:
1
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
AC:
0
AN:
53346
Middle Eastern (MID)
AF:
AC:
0
AN:
5722
European-Non Finnish (NFE)
AF:
AC:
4
AN:
1112012
Other (OTH)
AF:
AC:
1
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
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2
2
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4
0.00
0.20
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0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152222
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74368
show subpopulations
African (AFR)
AF:
AC:
1
AN:
41464
American (AMR)
AF:
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3464
East Asian (EAS)
AF:
AC:
0
AN:
5192
South Asian (SAS)
AF:
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68048
Other (OTH)
AF:
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Megalencephalic leukoencephalopathy with subcortical cysts 1 (3)
1
-
-
Megalencephalic leukoencephalopathy with subcortical cysts (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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