rs11568186

Variant names:

• chr22-50064115-G-A
• rs11568186
• NM_015166.4:c.978C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-50064115-G-A
• chr22-50064115-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015166.4(MLC1):​c.978C>T​(p.Cys326Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,506,278 control chromosomes in the GnomAD database, including 15,988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1210 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14778 hom.)
• Consequence: MLC1 NM_015166.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.23
• Publications: 13 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 22-50064115-G-A is Benign according to our data. Variant chr22-50064115-G-A is described in ClinVar as Benign. ClinVar VariationId is 129617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.978C>T	p.Cys326Cys	synonymous_variant	Exon 11 of 12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.978C>T	p.Cys326Cys	synonymous_variant	Exon 11 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.978C>T	p.Cys326Cys	synonymous_variant	Exon 11 of 12	1		ENSP00000379216.2
MLC1	ENST00000483836.1	n.335C>T		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes AF: 0.114 AC: 16913 AN: 148738 Hom.: 1210 Cov.: 33

Gnomad AFR AF: 0.0682

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.0747

Gnomad EAS AF: 0.0886

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.0780

Gnomad MID AF: 0.100

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.140

GnomAD2 exomes AF: 0.129 AC: 31409 AN: 243248 AF XY: 0.136

Gnomad AFR exome AF: 0.0693

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.0835

Gnomad EAS exome AF: 0.0921

Gnomad FIN exome AF: 0.0772

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.122 AC: 165321 AN: 1357424 Hom.: 14778 Cov.: 37 AF XY: 0.125 AC XY: 84293 AN XY: 675902

African (AFR) AF: 0.0588 AC: 1907 AN: 32416

American (AMR) AF: 0.115 AC: 4860 AN: 42258

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 1804 AN: 25328

East Asian (EAS) AF: 0.0901 AC: 3469 AN: 38508

South Asian (SAS) AF: 0.198 AC: 15946 AN: 80480

European-Finnish (FIN) AF: 0.0751 AC: 3596 AN: 47852

Middle Eastern (MID) AF: 0.112 AC: 588 AN: 5264

European-Non Finnish (NFE) AF: 0.123 AC: 126332 AN: 1028504

Other (OTH) AF: 0.120 AC: 6819 AN: 56814

GnomAD4 genome AF: 0.114 AC: 16917 AN: 148854 Hom.: 1210 Cov.: 33 AF XY: 0.114 AC XY: 8298 AN XY: 72758

African (AFR) AF: 0.0684 AC: 2796 AN: 40886

American (AMR) AF: 0.165 AC: 2456 AN: 14882

Ashkenazi Jewish (ASJ) AF: 0.0747 AC: 257 AN: 3442

East Asian (EAS) AF: 0.0889 AC: 445 AN: 5006

South Asian (SAS) AF: 0.212 AC: 968 AN: 4564

European-Finnish (FIN) AF: 0.0780 AC: 813 AN: 10422

Middle Eastern (MID) AF: 0.0903 AC: 26 AN: 288

European-Non Finnish (NFE) AF: 0.132 AC: 8773 AN: 66418

Other (OTH) AF: 0.138 AC: 286 AN: 2070

Alfa AF: 0.122 Hom.: 554

Bravo AF: 0.124

Asia WGS AF: 0.114 AC: 382 AN: 3370

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Megalencephalic leukoencephalopathy with subcortical cysts Benign:1

Nov 20, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.9
DANN	Benign	0.91
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11568186; hg19: chr22-50502544; COSMIC: COSV61116068;