Genetic Variant NM_015166.4:c.821C>G (chr22-50068506-G-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_015166.4(MLC1):c.821C>G(p.Thr274Arg) variant causes a missense change. 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. T274I) 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: 6.72

Publications

0 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: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_015166.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50068507-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4076991.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

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.821C>G	p.Thr274Arg	missense	Exon 10 of 12	NP_055981.1
MLC1	NM_001376472.1		c.821C>G	p.Thr274Arg	missense	Exon 9 of 11	NP_001363401.1
MLC1	NM_001376473.1		c.821C>G	p.Thr274Arg	missense	Exon 11 of 13	NP_001363402.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MLC1	ENST00000311597.10	TSL:1 MANE Select	c.821C>G	p.Thr274Arg	missense	Exon 10 of 12	ENSP00000310375.6
MLC1	ENST00000395876.6	TSL:1	c.821C>G	p.Thr274Arg	missense	Exon 10 of 12	ENSP00000379216.2
MLC1	ENST00000483836.1	TSL:2	n.178C>G		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.2

PhyloP100

6.7

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.86

MutPred

0.51

Gain of methylation at T274 (P = 0.0243)

MVP

0.91

MPC

0.96

ClinPred

0.99

GERP RS

4.6

Varity_R

0.73

gMVP

0.84

Mutation Taster

=59/41

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over