rs11568188

chr22-50064062-T-Cchr22-50064062-T-G

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.1031A>G(p.Asn344Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,480,250 control chromosomes in the GnomAD database, including 15,810 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N344N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.099 (1081 hom., cov: 32)
  • Exomes 𝑓: 0.12 (14729 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.631

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020861626).
• BP6: Variant 22-50064062-T-C is Benign according to our data. Variant chr22-50064062-T-C is described in ClinVar as [Benign]. Clinvar id is 21521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.1031A>G	p.Asn344Ser	missense_variant	11/12	ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.1031A>G	p.Asn344Ser	missense_variant	11/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.1031A>G	p.Asn344Ser	missense_variant	11/12	1		P1
MLC1	ENST00000483836.1	n.388A>G		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.0991 AC: 12277 AN: 123832 Hom.: 1081 Cov.: 32

Gnomad AFR AF: 0.0575

Gnomad AMI AF: 0.0916

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.0612

Gnomad EAS AF: 0.0826

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0642

Gnomad MID AF: 0.0985

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.113 AC: 26164 AN: 232170 Hom.: 2103 AF XY: 0.119 AC XY: 15008 AN XY: 126066

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0769

Gnomad EAS exome AF: 0.0790

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.0562

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.120 AC: 163080 AN: 1356324 Hom.: 14729 Cov.: 37 AF XY: 0.123 AC XY: 83100 AN XY: 675326

Gnomad4 AFR exome AF: 0.0581

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.0705

Gnomad4 EAS exome AF: 0.0892

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.0722

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.0991 AC: 12285 AN: 123926 Hom.: 1081 Cov.: 32 AF XY: 0.100 AC XY: 6042 AN XY: 60204

Gnomad4 AFR AF: 0.0578

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.0612

Gnomad4 EAS AF: 0.0829

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.0642

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.121

Alfa AF: 0.137 Hom.: 1041

Bravo AF: 0.124

TwinsUK AF: 0.131 AC: 487

ALSPAC AF: 0.136 AC: 525

ESP6500AA AF: 0.0663 AC: 292

ESP6500EA AF: 0.127 AC: 1094

ExAC AF: 0.0816 AC: 9819

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 12, 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 21, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	5.3
Dann	Benign	0.37
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0092	N
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.55	N;N
REVEL	Benign	0.18
Sift	Benign	0.83	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.0	B;B
Vest4		0.039
MPC		0.20
ClinPred		0.00075	T
GERP RS		1.7
Varity_R		0.025
gMVP		0.075

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs11568188; hg19: chr22-50502491; COSMIC: COSV61115728;