22-50064163-TAGCAGCAGC-TAGCAGCAGCAGCAGCAGC

Position:

• chr22-50064163-TAGCAGCAGC-TAGCAGCAGCAGCAGCAGC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP3

The ENST00000311597.10(MLC1):​c.929_930insGCTGCTGCT​(p.Leu308_Leu310dup) variant causes a inframe insertion 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L310L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MLC1 ENST00000311597.10 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.94

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in ENST00000311597.10

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4	c.929_930insGCTGCTGCT	p.Leu308_Leu310dup	inframe_insertion	11/12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.929_930insGCTGCTGCT	p.Leu308_Leu310dup	inframe_insertion	11/12	1	NM_015166.4	ENSP00000310375	P1
MLC1	ENST00000395876.6	c.929_930insGCTGCTGCT	p.Leu308_Leu310dup	inframe_insertion	11/12	1		ENSP00000379216	P1
MLC1	ENST00000483836.1	n.286_287insGCTGCTGCT		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Apr 24, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 10, 2022

This variant is not present in population databases (gnomAD no frequency). This variant, c.921_929dup, results in the insertion of 3 amino acid(s) of the MLC1 protein (p.Leu308_Leu310dup), but otherwise preserves the integrity of the reading frame. This variant has not been reported in the literature in individuals affected with MLC1-related conditions. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs761096481; hg19: chr22-50502592;