chr22-50064097-A-G

Variant names:

• chr22-50064097-A-G
• rs11568187
• NM_015166.4:c.996T>C

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.996T>C​(p.Ser332Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,509,286 control chromosomes in the GnomAD database, including 15,978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1211 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14767 hom.)
• Consequence: MLC1 NM_015166.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.730
• Publications: 10 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=-0.92).
• BP6: Variant 22-50064097-A-G is Benign according to our data. Variant chr22-50064097-A-G is described in ClinVar as Benign. ClinVar VariationId is 129618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	NM_015166.4	MANE Select	c.996T>C	p.Ser332Ser	synonymous	Exon 11 of 12	NP_055981.1
	MLC1	NM_001376472.1		c.996T>C	p.Ser332Ser	synonymous	Exon 10 of 11	NP_001363401.1
	MLC1	NM_001376473.1		c.996T>C	p.Ser332Ser	synonymous	Exon 12 of 13	NP_001363402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	ENST00000311597.10	TSL:1 MANE Select	c.996T>C	p.Ser332Ser	synonymous	Exon 11 of 12	ENSP00000310375.6
	MLC1	ENST00000395876.6	TSL:1	c.996T>C	p.Ser332Ser	synonymous	Exon 11 of 12	ENSP00000379216.2
	MLC1	ENST00000483836.1	TSL:2	n.353T>C		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.114 AC: 16890 AN: 148690 Hom.: 1211 Cov.: 33

Gnomad AFR AF: 0.0681

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.0744

Gnomad EAS AF: 0.0886

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.0779

Gnomad MID AF: 0.100

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.127 AC: 30672 AN: 242354 AF XY: 0.133

Gnomad AFR exome AF: 0.0674

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.0824

Gnomad EAS exome AF: 0.0903

Gnomad FIN exome AF: 0.0729

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.121 AC: 164943 AN: 1360478 Hom.: 14767 Cov.: 37 AF XY: 0.124 AC XY: 84066 AN XY: 677312

African (AFR) AF: 0.0586 AC: 1901 AN: 32460

American (AMR) AF: 0.115 AC: 4847 AN: 42302

Ashkenazi Jewish (ASJ) AF: 0.0708 AC: 1795 AN: 25360

East Asian (EAS) AF: 0.0898 AC: 3463 AN: 38546

South Asian (SAS) AF: 0.197 AC: 15928 AN: 80692

European-Finnish (FIN) AF: 0.0742 AC: 3577 AN: 48218

Middle Eastern (MID) AF: 0.111 AC: 582 AN: 5240

European-Non Finnish (NFE) AF: 0.122 AC: 126048 AN: 1030756

Other (OTH) AF: 0.120 AC: 6802 AN: 56904

GnomAD4 genome AF: 0.114 AC: 16894 AN: 148808 Hom.: 1211 Cov.: 33 AF XY: 0.114 AC XY: 8284 AN XY: 72734

African (AFR) AF: 0.0683 AC: 2791 AN: 40884

American (AMR) AF: 0.165 AC: 2458 AN: 14886

Ashkenazi Jewish (ASJ) AF: 0.0744 AC: 256 AN: 3442

East Asian (EAS) AF: 0.0889 AC: 445 AN: 5008

South Asian (SAS) AF: 0.212 AC: 966 AN: 4560

European-Finnish (FIN) AF: 0.0779 AC: 811 AN: 10414

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

European-Non Finnish (NFE) AF: 0.132 AC: 8760 AN: 66382

Other (OTH) AF: 0.137 AC: 284 AN: 2070

Alfa AF: 0.120 Hom.: 380

Bravo AF: 0.124

Asia WGS AF: 0.113 AC: 377 AN: 3364

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.79
PhyloP100		-0.73
Mutation Taster		=99/1	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: rs11568187; hg19: chr22-50502526; COSMIC: COSV61117529;