rs6010260

Positions:

chr22-50077414-C-A

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 links:

MLC1 (HGNC:):

MLC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
MLC1	NM_015166.4 linkuse as main transcript	c.512G>T	p.Cys171Phe	missense_variant	6/12	ENST00000311597.10	NP_055981.1	Q15049-1A0A024R4V4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MLC1	ENST00000311597.10 linkuse as main transcript	c.512G>T	p.Cys171Phe	missense_variant	6/12	1	NM_015166.4	ENSP00000310375.6	Q15049-1
MLC1	ENST00000395876.6 linkuse as main transcript	c.512G>T	p.Cys171Phe	missense_variant	6/12	1		ENSP00000379216.2	Q15049-1
MLC1	ENST00000442311.1 linkuse as main transcript	c.422G>T	p.Cys141Phe	missense_variant	5/8	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

GnomAD3 exomes

AF:

0.122

AC:

30477

AN:

250474

Hom.:

2078

AF XY:

0.128

AC XY:

17411

AN XY:

135682

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 SAS exome

AF:

0.222

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

Gnomad4 AFR exome

AF:

0.0684

Gnomad4 AMR exome

AF:

0.128

Gnomad4 ASJ exome

AF:

0.0640

Gnomad4 EAS exome

AF:

0.0985

Gnomad4 SAS exome

AF:

0.222

Gnomad4 FIN exome

AF:

0.0840

Gnomad4 NFE exome

AF:

0.127

Gnomad4 OTH exome

AF:

0.124

GnomAD4 genome

AF:

0.106

AC:

16094

AN:

152274

Hom.:

962

Cov.:

AF XY:

0.106

AC XY:

7897

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0678

Gnomad4 AMR

AF:

0.154

Gnomad4 ASJ

AF:

0.0596

Gnomad4 EAS

AF:

0.0882

Gnomad4 SAS

AF:

0.226

Gnomad4 FIN

AF:

0.0723

Gnomad4 NFE

AF:

0.118

Gnomad4 OTH

AF:

0.122

Alfa

AF:

0.112

Hom.:

750

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Megalencephalic leukoencephalopathy with subcortical cysts 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 21, 2019

- -

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

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;.

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over