22-50064040-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_015166.4(MLC1):c.1053T>C(p.Ala351Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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. A351A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00060 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 7 hom. )

Failed GnomAD Quality Control

Consequence

MLC1
NM_015166.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -6.10

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 22-50064040-A-G is Benign according to our data. Variant chr22-50064040-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.1 with no splicing effect.

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.1053T>C	p.Ala351Ala	synonymous	Exon 11 of 12	NP_055981.1
MLC1	NM_001376472.1		c.1053T>C	p.Ala351Ala	synonymous	Exon 10 of 11	NP_001363401.1
MLC1	NM_001376473.1		c.1053T>C	p.Ala351Ala	synonymous	Exon 12 of 13	NP_001363402.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MLC1	ENST00000311597.10	TSL:1 MANE Select	c.1053T>C	p.Ala351Ala	synonymous	Exon 11 of 12	ENSP00000310375.6
MLC1	ENST00000395876.6	TSL:1	c.1053T>C	p.Ala351Ala	synonymous	Exon 11 of 12	ENSP00000379216.2
MLC1	ENST00000483836.1	TSL:2	n.410T>C		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes

AF:

0.000602

AC:

AN:

137870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000234

Gnomad AMI

AF:

0.00377

Gnomad AMR

AF:

0.000957

Gnomad ASJ

AF:

0.000305

Gnomad EAS

AF:

0.000631

Gnomad SAS

AF:

0.00153

Gnomad FIN

AF:

0.000309

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000703

Gnomad OTH

AF:

0.00107

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000391

AC:

527

AN:

1348570

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

288

AN XY:

670410

show subpopulations

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

African (AFR)

AF:

0.000154

AC:

AN:

32432

American (AMR)

AF:

0.000667

AC:

AN:

41956

Ashkenazi Jewish (ASJ)

AF:

0.000198

AC:

AN:

25260

East Asian (EAS)

AF:

0.000260

AC:

AN:

38492

South Asian (SAS)

AF:

0.000777

AC:

AN:

77172

European-Finnish (FIN)

AF:

0.000715

AC:

AN:

43340

Middle Eastern (MID)

AF:

0.000430

AC:

AN:

4646

European-Non Finnish (NFE)

AF:

0.000357

AC:

367

AN:

1028756

Other (OTH)

AF:

0.000336

AC:

AN:

56516

⚠️ 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: 0.299

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000601

AC:

AN:

137996

Hom.:

Cov.:

AF XY:

0.000594

AC XY:

AN XY:

67378

show subpopulations

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

African (AFR)

AF:

0.000233

AC:

AN:

38632

American (AMR)

AF:

0.000955

AC:

AN:

13608

Ashkenazi Jewish (ASJ)

AF:

0.000305

AC:

AN:

3284

East Asian (EAS)

AF:

0.000632

AC:

AN:

4744

South Asian (SAS)

AF:

0.00153

AC:

AN:

3926

European-Finnish (FIN)

AF:

0.000309

AC:

AN:

9722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000704

AC:

AN:

61118

Other (OTH)

AF:

0.00106

AC:

AN:

1890

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000188116), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.387

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00793

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Jan 13, 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.

Sep 05, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Oct 08, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Megalencephalic leukoencephalopathy with subcortical cysts

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.11

(source)

DANN

Benign

0.60

PhyloP100

-6.1

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over