22-50074276-G-T

Position:

chr22-50074276-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_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 (★★).

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

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 -16 ACMG points.

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 [Likely_benign]. Clinvar id is 21525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50074276-G-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4 linkuse as main transcript	c.654C>A	p.Asn218Lys	missense_variant	8/12	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.654C>A	p.Asn218Lys	missense_variant	8/12	1	NM_015166.4	ENSP00000310375.6	Q15049-1
MLC1	ENST00000395876.6 linkuse as main transcript	c.654C>A	p.Asn218Lys	missense_variant	8/12	1		ENSP00000379216.2	Q15049-1
MLC1	ENST00000442311.1 linkuse as main transcript	c.564C>A	p.Asn188Lys	missense_variant	7/8	5		ENSP00000401385.1	A6PVC3
MLC1	ENST00000470008.1 linkuse as main transcript	n.134C>A		non_coding_transcript_exon_variant	2/3	3

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

GnomAD3 exomes

AF:

0.00286

AC:

717

AN:

250566

Hom.:

AF XY:

0.00306

AC XY:

415

AN XY:

135644

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 SAS 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

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00506

Gnomad4 NFE exome

AF:

0.00484

Gnomad4 OTH exome

AF:

0.00308

GnomAD4 genome

AF:

0.00304

AC:

463

AN:

152350

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

249

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00754

Gnomad4 NFE

AF:

0.00472

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00432

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

Significance: Benign/Likely 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MLC1: PP3, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Megalencephalic leukoencephalopathy with subcortical cysts 1

Benign:2

Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 28, 2018

- -

MLC1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Megalencephalic leukoencephalopathy with subcortical cysts

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

7.2

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D;.

Eigen

Benign

0.093

Eigen_PC

Benign

-0.076

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.3

M;M;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.3

D;D;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.94

MutPred

0.75

Gain of sheet (P = 0.0221);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

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

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