rs6010165

chr22-50076844-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015166.4(MLC1):c.594C>T(p.Tyr198=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,612,906 control chromosomes in the GnomAD database, including 13,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1077 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12783 hom.)
• Consequence: MLC1 NM_015166.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.110

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 22-50076844-G-A is Benign according to our data. Variant chr22-50076844-G-A is described in ClinVar as [Benign]. Clinvar id is 129614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.594C>T	p.Tyr198=	synonymous_variant	7/12	ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.594C>T	p.Tyr198=	synonymous_variant	7/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.594C>T	p.Tyr198=	synonymous_variant	7/12	1		P1
MLC1	ENST00000442311.1	c.504C>T	p.Tyr168=	synonymous_variant	6/8	5

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17631 AN: 152086 Hom.: 1073 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: 0.0891

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0724

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.124 AC: 31262 AN: 251116 Hom.: 2155 AF XY: 0.131 AC XY: 17723 AN XY: 135714

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.0669

Gnomad EAS exome AF: 0.0878

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.0801

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.129 AC: 187899 AN: 1460702 Hom.: 12783 Cov.: 32 AF XY: 0.132 AC XY: 95684 AN XY: 726718

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.0639

Gnomad4 EAS exome AF: 0.0988

Gnomad4 SAS exome AF: 0.222

Gnomad4 FIN exome AF: 0.0842

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.127

GnomAD4 genome AF: 0.116 AC: 17648 AN: 152204 Hom.: 1077 Cov.: 33 AF XY: 0.116 AC XY: 8648 AN XY: 74436

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.0597

Gnomad4 EAS AF: 0.0893

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.0724

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.129

Alfa AF: 0.119 Hom.: 1482

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 specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Megalencephalic leukoencephalopathy with subcortical cysts Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.54
Dann	Benign	0.24

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

Other links and lift over

dbSNP: rs6010165; hg19: chr22-50515273; COSMIC: COSV61117553; COSMIC: COSV61117553;