NM_015166.4:c.1008G>T
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2
The NM_015166.4(MLC1):c.1008G>T(p.Gln336His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,609,726 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q336R) has been classified as Uncertain significance.
Frequency
Consequence
NM_015166.4 missense
Scores
Clinical Significance
Conservation
Publications
- megalencephalic leukoencephalopathy with subcortical cysts 1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Myriad Women’s Health
- megalencephalic leukoencephalopathy with subcortical cystsInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLC1 | NM_015166.4 | c.1008G>T | p.Gln336His | missense_variant | Exon 11 of 12 | ENST00000311597.10 | NP_055981.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLC1 | ENST00000311597.10 | c.1008G>T | p.Gln336His | missense_variant | Exon 11 of 12 | 1 | NM_015166.4 | ENSP00000310375.6 | ||
MLC1 | ENST00000395876.6 | c.1008G>T | p.Gln336His | missense_variant | Exon 11 of 12 | 1 | ENSP00000379216.2 | |||
MLC1 | ENST00000483836.1 | n.365G>T | non_coding_transcript_exon_variant | Exon 4 of 5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000178 AC: 27AN: 151604Hom.: 2 Cov.: 34 show subpopulations
GnomAD2 exomes AF: 0.000190 AC: 47AN: 247902 AF XY: 0.000178 show subpopulations
GnomAD4 exome AF: 0.000147 AC: 214AN: 1458122Hom.: 6 Cov.: 39 AF XY: 0.000135 AC XY: 98AN XY: 725594 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000178 AC: 27AN: 151604Hom.: 2 Cov.: 34 AF XY: 0.000203 AC XY: 15AN XY: 74032 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Megalencephalic leukoencephalopathy with subcortical cysts 1 Uncertain:3
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This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided Uncertain:2
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This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 336 of the MLC1 protein (p.Gln336His). This variant is present in population databases (rs139336504, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MLC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 547978). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Inborn genetic diseases Uncertain:1
The c.1008G>T (p.Q336H) alteration is located in exon 11 (coding exon 10) of the MLC1 gene. This alteration results from a G to T substitution at nucleotide position 1008, causing the glutamine (Q) at amino acid position 336 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at