22-50064163-TAGCAGCAGC-TAGCAGCAGCAGCAGCAGC

Variant names:

• chr22-50064163-T-TAGCAGCAGC
• rs761096481
• NM_015166.4:c.921_929dupGCTGCTGCT

Variant summary

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

The NM_015166.4(MLC1):​c.921_929dupGCTGCTGCT​(p.Leu308_Leu310dup) variant causes a disruptive 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 (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: MLC1 NM_015166.4 disruptive_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 NM_015166.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.921_929dupGCTGCTGCT	p.Leu308_Leu310dup	disruptive_inframe_insertion	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.921_929dupGCTGCTGCT	p.Leu308_Leu310dup	disruptive_inframe_insertion	Exon 11 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.921_929dupGCTGCTGCT	p.Leu308_Leu310dup	disruptive_inframe_insertion	Exon 11 of 12	1		ENSP00000379216.2
MLC1	ENST00000483836.1	n.278_286dupGCTGCTGCT		non_coding_transcript_exon_variant	Exon 4 of 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

Apr 24, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Feb 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant has not been reported in the literature in individuals affected with MLC1-related conditions. 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. -

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;