rs6010260

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015166.4(MLC1):c.512G>T(p.Cys171Phe) variant causes a missense change. The variant allele was found at a frequency of 0.126 in 1,613,234 control chromosomes in the GnomAD database, including 13,601 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 962 hom., cov: 33)

Exomes 𝑓: 0.13 ( 12639 hom. )

Consequence

MLC1
NM_015166.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.82

Publications

26 publications found

Variant links:

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), Ambry Genetics, G2P, Myriad Women’s Health
megalencephalic leukoencephalopathy with subcortical cysts
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MLC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017397702).

BP6

Variant 22-50077414-C-A is Benign according to our data. Variant chr22-50077414-C-A is described in ClinVar as Benign. ClinVar VariationId is 21524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4 link	c.512G>T	p.Cys171Phe	missense_variant	Exon 6 of 12	ENST00000311597.10	NP_055981.1	Q15049-1A0A024R4V4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MLC1	ENST00000311597.10 link	c.512G>T	p.Cys171Phe	missense_variant	Exon 6 of 12	1	NM_015166.4	ENSP00000310375.6	Q15049-1
MLC1	ENST00000395876.6 link	c.512G>T	p.Cys171Phe	missense_variant	Exon 6 of 12	1		ENSP00000379216.2	Q15049-1
MLC1	ENST00000442311.1 link	c.422G>T	p.Cys141Phe	missense_variant	Exon 5 of 8	5		ENSP00000401385.1	A6PVC3

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16089

AN:

152156

Hom.:

961

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0676

Gnomad AMI

AF:

0.109

Gnomad AMR

AF:

0.154

Gnomad ASJ

AF:

0.0596

Gnomad EAS

AF:

0.0880

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.0723

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.124

GnomAD2 exomes

AF:

0.122

AC:

30477

AN:

250474

AF XY:

0.128

show subpopulations

Gnomad AFR exome

AF:

0.0670

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.0669

Gnomad EAS exome

AF:

0.0877

Gnomad FIN exome

AF:

0.0801

Gnomad NFE exome

AF:

0.121

Gnomad OTH exome

AF:

0.125

GnomAD4 exome

AF:

0.128

AC:

186526

AN:

1460960

Hom.:

12639

Cov.:

AF XY:

0.131

AC XY:

95087

AN XY:

726798

show subpopulations

African (AFR)

AF:

0.0684

AC:

2290

AN:

33474

American (AMR)

AF:

0.128

AC:

5704

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0640

AC:

1672

AN:

26134

East Asian (EAS)

AF:

0.0985

AC:

3911

AN:

39688

South Asian (SAS)

AF:

0.222

AC:

19161

AN:

86192

European-Finnish (FIN)

AF:

0.0840

AC:

4467

AN:

53172

Middle Eastern (MID)

AF:

0.136

AC:

782

AN:

5740

European-Non Finnish (NFE)

AF:

0.127

AC:

141046

AN:

1111486

Other (OTH)

AF:

0.124

AC:

7493

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

8446

16892

25337

33783

42229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5210

10420

15630

20840

26050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.106

AC:

16094

AN:

152274

Hom.:

962

Cov.:

AF XY:

0.106

AC XY:

7897

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0678

AC:

2817

AN:

41552

American (AMR)

AF:

0.154

AC:

2354

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0596

AC:

207

AN:

3472

East Asian (EAS)

AF:

0.0882

AC:

457

AN:

5184

South Asian (SAS)

AF:

0.226

AC:

1089

AN:

4826

European-Finnish (FIN)

AF:

0.0723

AC:

768

AN:

10620

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8016

AN:

67998

Other (OTH)

AF:

0.122

AC:

258

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

740

1480

2221

2961

3701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

190

380

570

760

950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.112

Hom.:

1003

Bravo

AF:

0.108

TwinsUK

AF:

0.129

AC:

479

ALSPAC

AF:

0.128

AC:

492

ESP6500AA

AF:

0.0708

AC:

312

ESP6500EA

AF:

0.118

AC:

1019

ExAC

AF:

0.123

AC:

14963

Asia WGS

AF:

0.146

AC:

506

AN:

3478

EpiCase

AF:

0.117

EpiControl

AF:

0.123

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Megalencephalic leukoencephalopathy with subcortical cysts 1

Benign:2

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Megalencephalic leukoencephalopathy with subcortical cysts

Benign:1

Nov 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.46

T;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.52

.;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.8

L;L;.

PhyloP100

3.8

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-11

D;D;D

REVEL

Benign

0.23

Sift

Benign

0.034

D;D;D

Sift4G

Benign

0.14

T;T;T

Polyphen

0.18

B;B;.

Vest4

0.13

MPC

0.82

ClinPred

0.065

GERP RS

3.3

Varity_R

0.69

gMVP

0.82

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over