rs11568188

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1031A>G(p.Asn344Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,480,250 control chromosomes in the GnomAD database, including 15,810 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N344N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.099 ( 1081 hom., cov: 32)

Exomes 𝑓: 0.12 ( 14729 hom. )

Consequence

MLC1
NM_015166.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.631

Publications

19 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=0.0020861626).

BP6

Variant 22-50064062-T-C is Benign according to our data. Variant chr22-50064062-T-C is described in ClinVar as Benign. ClinVar VariationId is 21521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4 link	c.1031A>G	p.Asn344Ser	missense_variant	Exon 11 of 12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MLC1	ENST00000311597.10 link	c.1031A>G	p.Asn344Ser	missense_variant	Exon 11 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6 link	c.1031A>G	p.Asn344Ser	missense_variant	Exon 11 of 12	1		ENSP00000379216.2
MLC1	ENST00000483836.1 link	n.388A>G		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0991

AC:

12277

AN:

123832

Hom.:

1081

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0575

Gnomad AMI

AF:

0.0916

Gnomad AMR

AF:

0.157

Gnomad ASJ

AF:

0.0612

Gnomad EAS

AF:

0.0826

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.0642

Gnomad MID

AF:

0.0985

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.123

GnomAD2 exomes

AF:

0.113

AC:

26164

AN:

232170

AF XY:

0.119

show subpopulations

Gnomad AFR exome

AF:

0.0551

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.0769

Gnomad EAS exome

AF:

0.0790

Gnomad FIN exome

AF:

0.0562

Gnomad NFE exome

AF:

0.114

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.120

AC:

163080

AN:

1356324

Hom.:

14729

Cov.:

AF XY:

0.123

AC XY:

83100

AN XY:

675326

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0581

AC:

1879

AN:

32366

American (AMR)

AF:

0.113

AC:

4772

AN:

42184

Ashkenazi Jewish (ASJ)

AF:

0.0705

AC:

1787

AN:

25338

East Asian (EAS)

AF:

0.0892

AC:

3434

AN:

38504

South Asian (SAS)

AF:

0.196

AC:

15762

AN:

80562

European-Finnish (FIN)

AF:

0.0722

AC:

3334

AN:

46152

Middle Eastern (MID)

AF:

0.108

AC:

536

AN:

4944

European-Non Finnish (NFE)

AF:

0.121

AC:

124838

AN:

1029484

Other (OTH)

AF:

0.119

AC:

6738

AN:

56790

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.373

Heterozygous variant carriers

7459

14918

22377

29836

37295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4202

8404

12606

16808

21010

<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:

0.0991

AC:

12285

AN:

123926

Hom.:

1081

Cov.:

AF XY:

0.100

AC XY:

6042

AN XY:

60204

show subpopulations

African (AFR)

AF:

0.0578

AC:

1974

AN:

34150

American (AMR)

AF:

0.157

AC:

1898

AN:

12094

Ashkenazi Jewish (ASJ)

AF:

0.0612

AC:

183

AN:

2988

East Asian (EAS)

AF:

0.0829

AC:

345

AN:

4160

South Asian (SAS)

AF:

0.200

AC:

702

AN:

3516

European-Finnish (FIN)

AF:

0.0642

AC:

552

AN:

8594

Middle Eastern (MID)

AF:

0.0868

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.114

AC:

6335

AN:

55728

Other (OTH)

AF:

0.121

AC:

207

AN:

1712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

465

930

1396

1861

2326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.141

Hom.:

1499

Bravo

AF:

0.124

TwinsUK

AF:

0.131

AC:

487

ALSPAC

AF:

0.136

AC:

525

ESP6500AA

AF:

0.0663

AC:

292

ESP6500EA

AF:

0.127

AC:

1094

ExAC

AF:

0.0816

AC:

9819

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 20, 2018

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

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Megalencephalic leukoencephalopathy with subcortical cysts 1

Benign:2

Sep 05, 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

0.056

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.55

CADD

Benign

5.3

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.019

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.11

.;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

N;N

PhyloP100

0.63

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.55

N;N

REVEL

Benign

0.18

Sift

Benign

0.83

T;T

Sift4G

Benign

0.76

T;T

Polyphen

0.0

B;B

Vest4

0.039

MPC

0.20

ClinPred

0.00075

GERP RS

1.7

Varity_R

0.025

gMVP

0.075

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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