22-50080389-GGG-AGA

Variant names:

• chr22-50080389-GGG-AGA
• NM_015166.4:c.274_276delCCCinsTCT
• MLC1 p.Pro92Ser

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1_Very_Strong PM1 PM5

The NM_015166.4(MLC1):​c.274_276delCCCinsTCT​(p.Pro92Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P92L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.19
• Publications: 0 publications found

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]

MLC1 Gene-Disease associations (from GenCC):

• megalencephalic leukoencephalopathy with subcortical cysts 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P, Ambry Genetics
• megalencephalic leukoencephalopathy with subcortical cysts

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS1: Transcript NM_015166.4 (MLC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_015166.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50080390-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1524959.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015166.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	NM_015166.4	MANE Select	c.274_276delCCCinsTCT	p.Pro92Ser	missense	N/A	NP_055981.1	Q15049-1
	MLC1	NM_001376472.1		c.274_276delCCCinsTCT	p.Pro92Ser	missense	N/A	NP_001363401.1	Q15049-1
	MLC1	NM_001376473.1		c.274_276delCCCinsTCT	p.Pro92Ser	missense	N/A	NP_001363402.1	Q15049-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	ENST00000311597.10	TSL:1 MANE Select	c.274_276delCCCinsTCT	p.Pro92Ser	missense	N/A	ENSP00000310375.6	Q15049-1
	MLC1	ENST00000395876.6	TSL:1	c.274_276delCCCinsTCT	p.Pro92Ser	missense	N/A	ENSP00000379216.2	Q15049-1
	MLC1	ENST00000879262.1		c.274_276delCCCinsTCT	p.Pro92Ser	missense	N/A	ENSP00000549321.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-50518818;