rs80358241

Positions:

• chr22-50084767-AG-A
• chr22-50084767-AG-AGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015166.4(MLC1):​c.135del​(p.Cys46AlafsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLC1 NM_015166.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -2.59

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50084767-AG-A is Pathogenic according to our data. Variant chr22-50084767-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 2138460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50084767-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4	c.135del	p.Cys46AlafsTer12	frameshift_variant	2/12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.135del	p.Cys46AlafsTer12	frameshift_variant	2/12	1	NM_015166.4	ENSP00000310375	P1
MLC1	ENST00000395876.6	c.135del	p.Cys46AlafsTer12	frameshift_variant	2/12	1		ENSP00000379216	P1
MLC1	ENST00000442311.1	c.135del	p.Cys46AlafsTer12	frameshift_variant	2/8	5		ENSP00000401385

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2022

This variant is not present in population databases (gnomAD no frequency). 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 premature translational stop signal has been observed in individuals with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 25497041, 28588848, 28840990). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80358241; hg19: chr22-50523196;