dbSNP rs1258044054: MLC1:p.Leu135Arg (chr22-50079937-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_015166.4(MLC1):c.404T>G(p.Leu135Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L135P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MLC1
NM_015166.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.34

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4 link	c.404T>G	p.Leu135Arg	missense_variant	Exon 5 of 12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MLC1	ENST00000311597.10 link	c.404T>G	p.Leu135Arg	missense_variant	Exon 5 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6 link	c.404T>G	p.Leu135Arg	missense_variant	Exon 5 of 12	1		ENSP00000379216.2
MLC1	ENST00000442311.1 link	c.314T>G	p.Leu105Arg	missense_variant	Exon 4 of 8	5		ENSP00000401385.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251480

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

0.55

N;N;.

PhyloP100

8.3

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.91

P;P;.

Vest4

0.92

MutPred

0.52

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;

MVP

0.95

MPC

1.1

ClinPred

0.99

GERP RS

5.1

Varity_R

0.75

gMVP

0.92

Mutation Taster

=37/63

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over