rs184241759

Positions:

• chr22-50084838-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015166.4(MLC1):​c.65G>A​(p.Arg22Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,626 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 3.12

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0071160197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4	c.65G>A	p.Arg22Gln	missense_variant	2/12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.65G>A	p.Arg22Gln	missense_variant	2/12	1	NM_015166.4	ENSP00000310375	P1
MLC1	ENST00000395876.6	c.65G>A	p.Arg22Gln	missense_variant	2/12	1		ENSP00000379216	P1
MLC1	ENST00000442311.1	c.65G>A	p.Arg22Gln	missense_variant	2/8	5		ENSP00000401385

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000471 AC: 118 AN: 250418 Hom.: 0 AF XY: 0.000435 AC XY: 59 AN XY: 135560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00436

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000163 AC: 238 AN: 1461292 Hom.: 1 Cov.: 32 AF XY: 0.000184 AC XY: 134 AN XY: 726984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00259

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74502

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.000276

ExAC AF: 0.000552 AC: 67

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 29, 2017	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 22 of the MLC1 protein (p.Arg22Gln). This variant is present in population databases (rs184241759, gnomAD 0.5%). This missense change has been observed in individual(s) with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 21160490). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225412). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MLC1 function (PMID: 22416245). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2017	The R22Q variant in the MLC1 gene has been reported previously in a patient with megalencephalic leukoencephalopathy with subcortical cysts, however, this patient was not found to have a pathogenic variant on the other MLC1 allele (Wang et al., 2011). The R22Q variant is observed in 43/8556 (0.5%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016). The R22Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. While transfection studies indicate that the R22Q variant affected intracellular protein localization, protein/mRNA expression levels for R22Q were comparable with wild type (Xie et al., 2012). Therefore, we interpret R22Q as a variant of uncertain significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 14, 2022

Variant summary: MLC1 c.65G>A (p.Arg22Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 250418 control chromosomes (gnomAD), predominantly at a frequency of 0.0044 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLC1 causing Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.65G>A has been reported in the literature in individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1, including one sibling pair that carried a second pathogenic variant in trans (Wang_2011). The variant was also found in one affected individual with a benign variant on the second allele (Wang_2011) and in one individual that carried a likely pathogenic variant in cis and another potentially pathogenic variant (c.772-1G>C) in trans (Cao_2016). These data indicate that the variant may be associated with disease. One functional study demonstrated that the variant protein is mislocalized in the cell, with 8.26% of the protein being trafficked to the cell surface, and the remainder being trapped in the endoplasmic reticulum (Xie_2012). Five ClinVar submitters have assessed the variant since 2014: four classified the variant as of uncertain significance, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Megalencephalic leukoencephalopathy with subcortical cysts Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;.
Eigen	Benign	-0.0059
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.0071	T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.22	B;B;.
Vest4		0.73
MVP		0.88
MPC		0.29
ClinPred		0.16	T
GERP RS		5.5
Varity_R		0.34
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs184241759; hg19: chr22-50523267;