rs11568187

Positions:

• chr22-50064097-A-G

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.996T>C​(p.Ser332=) 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:7
• Conservation: PhyloP100: -0.730

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=-0.92).
• BP6: Variant 22-50064097-A-G is Benign according to our data. Variant chr22-50064097-A-G is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.996T>C	p.Ser332=	synonymous_variant	11/12	ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.996T>C	p.Ser332=	synonymous_variant	11/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.996T>C	p.Ser332=	synonymous_variant	11/12	1		P1
MLC1	ENST00000483836.1	n.353T>C		non_coding_transcript_exon_variant	4/5	2

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

GnomAD3 exomes AF: 0.127 AC: 30672 AN: 242354 Hom.: 2310 AF XY: 0.133 AC XY: 17561 AN XY: 131568

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 SAS exome AF: 0.213

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

Gnomad4 AFR exome AF: 0.0586

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.0708

Gnomad4 EAS exome AF: 0.0898

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.0742

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.120

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

Gnomad4 AFR AF: 0.0683

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.0744

Gnomad4 EAS AF: 0.0889

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.0779

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.137

Alfa AF: 0.121 Hom.: 379

Bravo AF: 0.124

Asia WGS AF: 0.113 AC: 377 AN: 3364

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 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	Sep 20, 2018	- -

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	-0.92
CADD	Benign	1.8
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs11568187; hg19: chr22-50502526; COSMIC: COSV61117529;