rs794729233

Variant names:

• chr22-50083127-AC-A
• rs794729233
• NM_015166.4:c.223delG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015166.4(MLC1):​c.223delG​(p.Val75CysfsTer22) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLC1 NM_015166.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.44

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 11 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 22-50083127-AC-A is Pathogenic according to our data. Variant chr22-50083127-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 202208.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.223delG	p.Val75CysfsTer22	frameshift_variant	Exon 3 of 12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.223delG	p.Val75CysfsTer22	frameshift_variant	Exon 3 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.223delG	p.Val75CysfsTer22	frameshift_variant	Exon 3 of 12	1		ENSP00000379216.2
MLC1	ENST00000442311.1	c.177+1598delG		intron_variant	Intron 2 of 7	5		ENSP00000401385.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:1

Jan 03, 2014

Mendelics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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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: rs794729233; hg19: chr22-50521556;