22-50074296-C-G

Variant names:

• chr22-50074296-C-G
• rs281875317
• NM_015166.4:c.634G>C

Variant summary

Our verdict is Pathogenic. The variant received 28 ACMG points: 28P and 0B. PS1_Very_Strong PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_015166.4(MLC1):​c.634G>C​(p.Gly212Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005381204: One publication reports experimental evidence evaluating an impact on protein function showing reduced expression of the MLC1 protein at the plasma membrane in vitro (e.g. Teijido_2004), however, does not allow convincing conclusions about the variant effect.". 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. G212E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.90
• Publications: 6 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 28 ACMG points.

• PS1: Transcript NM_015166.4 (MLC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005381204: One publication reports experimental evidence evaluating an impact on protein function showing reduced expression of the MLC1 protein at the plasma membrane in vitro (e.g. Teijido_2004), however, does not allow convincing conclusions about the variant effect.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50074295-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2737052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 22-50074296-C-G is Pathogenic according to our data. Variant chr22-50074296-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 553381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.634G>C	p.Gly212Arg	missense	Exon 8 of 12	NP_055981.1	Q15049-1
	MLC1	NM_001376472.1		c.634G>C	p.Gly212Arg	missense	Exon 7 of 11	NP_001363401.1	Q15049-1
	MLC1	NM_001376473.1		c.634G>C	p.Gly212Arg	missense	Exon 9 of 13	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.634G>C	p.Gly212Arg	missense	Exon 8 of 12	ENSP00000310375.6	Q15049-1
	MLC1	ENST00000395876.6	TSL:1	c.634G>C	p.Gly212Arg	missense	Exon 8 of 12	ENSP00000379216.2	Q15049-1
	MLC1	ENST00000879262.1		c.634G>C	p.Gly212Arg	missense	Exon 9 of 13	ENSP00000549321.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Megalencephalic leukoencephalopathy with subcortical cysts 1 (2)
1	-	-	Megalencephalic leukoencephalopathy with subcortical cysts (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.96		Loss of sheet (P = 0.007)
MVP		0.95
MPC		0.98
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.74
gMVP		0.88
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs281875317; hg19: chr22-50512725;