22-50076841-T-C

Variant names:

• chr22-50076841-T-C
• rs6010164
• NM_015166.4:c.597A>G

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.597A>G​(p.Ser199Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,612,712 control chromosomes in the GnomAD database, including 13,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1076 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12807 hom.)
• Consequence: MLC1 NM_015166.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005492
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.43
• Publications: 14 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=-0.78).
• BP6: Variant 22-50076841-T-C is Benign according to our data. Variant chr22-50076841-T-C is described in ClinVar as Benign. ClinVar VariationId is 129615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 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.597A>G	p.Ser199Ser	splice_region synonymous	Exon 7 of 12	NP_055981.1
	MLC1	NM_001376472.1		c.597A>G	p.Ser199Ser	splice_region synonymous	Exon 6 of 11	NP_001363401.1
	MLC1	NM_001376473.1		c.597A>G	p.Ser199Ser	splice_region synonymous	Exon 8 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.597A>G	p.Ser199Ser	splice_region synonymous	Exon 7 of 12	ENSP00000310375.6
	MLC1	ENST00000395876.6	TSL:1	c.597A>G	p.Ser199Ser	splice_region synonymous	Exon 7 of 12	ENSP00000379216.2
	MLC1	ENST00000442311.1	TSL:5	c.507A>G	p.Ser169Ser	splice_region synonymous	Exon 6 of 8	ENSP00000401385.1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17630 AN: 152046 Hom.: 1072 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.0889

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0725

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.125 AC: 31277 AN: 251120 AF XY: 0.131

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.0669

Gnomad EAS exome AF: 0.0879

Gnomad FIN exome AF: 0.0801

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.129 AC: 188041 AN: 1460548 Hom.: 12807 Cov.: 32 AF XY: 0.132 AC XY: 95766 AN XY: 726692

African (AFR) AF: 0.102 AC: 3428 AN: 33454

American (AMR) AF: 0.130 AC: 5800 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 1669 AN: 26128

East Asian (EAS) AF: 0.0990 AC: 3929 AN: 39686

South Asian (SAS) AF: 0.222 AC: 19178 AN: 86218

European-Finnish (FIN) AF: 0.0843 AC: 4495 AN: 53352

Middle Eastern (MID) AF: 0.139 AC: 802 AN: 5758

European-Non Finnish (NFE) AF: 0.127 AC: 141098 AN: 1110896

Other (OTH) AF: 0.127 AC: 7642 AN: 60342

GnomAD4 genome AF: 0.116 AC: 17647 AN: 152164 Hom.: 1076 Cov.: 33 AF XY: 0.116 AC XY: 8646 AN XY: 74412

African (AFR) AF: 0.104 AC: 4308 AN: 41520

American (AMR) AF: 0.157 AC: 2394 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 207 AN: 3468

East Asian (EAS) AF: 0.0891 AC: 461 AN: 5174

South Asian (SAS) AF: 0.225 AC: 1087 AN: 4822

European-Finnish (FIN) AF: 0.0725 AC: 768 AN: 10600

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.118 AC: 8018 AN: 67980

Other (OTH) AF: 0.129 AC: 273 AN: 2110

Alfa AF: 0.119 Hom.: 2680

Bravo AF: 0.119

Asia WGS AF: 0.147 AC: 510 AN: 3478

EpiCase AF: 0.117

EpiControl AF: 0.123

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 04, 2021

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Jun 10, 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

Dec 09, 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	-0.78
CADD	Benign	0.024
DANN	Benign	0.36
PhyloP100		-1.4
Mutation Taster		=50/50	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.010
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: rs6010164; hg19: chr22-50515270; COSMIC: COSV61118238; COSMIC: COSV61118238;