rs11568185

Positions:

• chr22-50064207-G-A
• chr22-50064207-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015166.4(MLC1):​c.895-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,585,140 control chromosomes in the GnomAD database, including 17,829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1267 hom., cov: 34)
  • Exomes 𝑓: 0.15 (16562 hom.)
• Consequence: MLC1 NM_015166.4 intron
• Scores: Splicing: ADA: 0.00002558
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.83

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-50064207-G-A is Benign according to our data. Variant chr22-50064207-G-A is described in ClinVar as [Benign]. Clinvar id is 129616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4	c.895-9C>T		intron_variant		ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.895-9C>T		intron_variant		1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.895-9C>T		intron_variant		1		ENSP00000379216.2
MLC1	ENST00000483836.1	n.252-9C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18569 AN: 152096 Hom.: 1266 Cov.: 34

Gnomad AFR AF: 0.0745

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.0980

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.0857

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.127 AC: 26554 AN: 208606 Hom.: 1835 AF XY: 0.134 AC XY: 15340 AN XY: 114588

Gnomad AFR exome AF: 0.0646

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.0835

Gnomad EAS exome AF: 0.0870

Gnomad SAS exome AF: 0.210

Gnomad FIN exome AF: 0.0791

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.149 AC: 213518 AN: 1432924 Hom.: 16562 Cov.: 38 AF XY: 0.151 AC XY: 107668 AN XY: 712024

Gnomad4 AFR exome AF: 0.0726

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.0837

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.0950

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.122 AC: 18576 AN: 152216 Hom.: 1267 Cov.: 34 AF XY: 0.123 AC XY: 9121 AN XY: 74410

Gnomad4 AFR AF: 0.0747

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.0781

Gnomad4 EAS AF: 0.0984

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.0857

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.146

Alfa AF: 0.122 Hom.: 236

Bravo AF: 0.124

Asia WGS AF: 0.156 AC: 539 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

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	PreventionGenetics, part of Exact Sciences	-	- -

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

Megalencephalic leukoencephalopathy with subcortical cysts Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.10
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs11568185; hg19: chr22-50502636;