Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_015166.4(MLC1):c.654C>A(p.Asn218Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,614,094 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N218N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 13 hom. )

Consequence

MLC1
NM_015166.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0900

Publications

14 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 -14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_015166.4

BP4

Computational evidence support a benign effect (MetaRNN=0.014566392).

BP6

Variant 22-50074276-G-T is Benign according to our data. Variant chr22-50074276-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 13 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MLC1	NM_015166.4	MANE Select	c.654C>A	p.Asn218Lys	missense	Exon 8 of 12	NP_055981.1
MLC1	NM_001376472.1		c.654C>A	p.Asn218Lys	missense	Exon 7 of 11	NP_001363401.1
MLC1	NM_001376473.1		c.654C>A	p.Asn218Lys	missense	Exon 9 of 13	NP_001363402.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MLC1	ENST00000311597.10	TSL:1 MANE Select	c.654C>A	p.Asn218Lys	missense	Exon 8 of 12	ENSP00000310375.6
MLC1	ENST00000395876.6	TSL:1	c.654C>A	p.Asn218Lys	missense	Exon 8 of 12	ENSP00000379216.2
MLC1	ENST00000442311.1	TSL:5	c.564C>A	p.Asn188Lys	missense	Exon 7 of 8	ENSP00000401385.1

Frequencies

GnomAD3 genomes

AF:

0.00304

AC:

463

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00472

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00286

AC:

717

AN:

250566

AF XY:

0.00306

show subpopulations

Gnomad AFR exome

AF:

0.000803

Gnomad AMR exome

AF:

0.000724

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00584

Gnomad NFE exome

AF:

0.00463

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00406

AC:

5936

AN:

1461744

Hom.:

Cov.:

AF XY:

0.00404

AC XY:

2938

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33480

American (AMR)

AF:

0.000671

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00506

AC:

270

AN:

53352

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00484

AC:

5387

AN:

1111984

Other (OTH)

AF:

0.00308

AC:

186

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

336

672

1009

1345

1681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

194

388

582

776

970

<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:

0.00304

AC:

463

AN:

152350

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

249

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000842

AC:

AN:

41586

American (AMR)

AF:

0.00137

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00754

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00472

AC:

321

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00421

Hom.:

Bravo

AF:

0.00256

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00268

AC:

325

EpiCase

AF:

0.00382

EpiControl

AF:

0.00367

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Megalencephalic leukoencephalopathy with subcortical cysts 1 (2)

Megalencephalic leukoencephalopathy with subcortical cysts (1)

MLC1-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

7.2

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Benign

0.093

Eigen_PC

Benign

-0.076

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.3

PhyloP100

0.090

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.75

Gain of sheet (P = 0.0221)

MVP

0.86

MPC

0.96

ClinPred

0.047

GERP RS

-1.3

Varity_R

0.73

gMVP

0.87

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over