22-50064040-A-G

Variant names:

• chr22-50064040-A-G
• rs11568190
• NM_015166.4:c.1053T>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_015166.4(MLC1):​c.1053T>C​(p.Ala351Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLC1 NM_015166.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -6.10

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 22-50064040-A-G is Benign according to our data. Variant chr22-50064040-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50064040-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.1 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.1053T>C	p.Ala351Ala	synonymous_variant	Exon 11 of 12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.1053T>C	p.Ala351Ala	synonymous_variant	Exon 11 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.1053T>C	p.Ala351Ala	synonymous_variant	Exon 11 of 12	1		ENSP00000379216.2
MLC1	ENST00000483836.1	n.410T>C		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes AF: 0.000602 AC: 83 AN: 137870 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000234

Gnomad AMI AF: 0.00377

Gnomad AMR AF: 0.000957

Gnomad ASJ AF: 0.000305

Gnomad EAS AF: 0.000631

Gnomad SAS AF: 0.00153

Gnomad FIN AF: 0.000309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000703

Gnomad OTH AF: 0.00107

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000391 AC: 527 AN: 1348570 Hom.: 7 Cov.: 36 AF XY: 0.000430 AC XY: 288 AN XY: 670410

Gnomad4 AFR exome AF: 0.000154

Gnomad4 AMR exome AF: 0.000667

Gnomad4 ASJ exome AF: 0.000198

Gnomad4 EAS exome AF: 0.000260

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.000715

Gnomad4 NFE exome AF: 0.000357

Gnomad4 OTH exome AF: 0.000336

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000601 AC: 83 AN: 137996 Hom.: 2 Cov.: 33 AF XY: 0.000594 AC XY: 40 AN XY: 67378

Gnomad4 AFR AF: 0.000233

Gnomad4 AMR AF: 0.000955

Gnomad4 ASJ AF: 0.000305

Gnomad4 EAS AF: 0.000632

Gnomad4 SAS AF: 0.00153

Gnomad4 FIN AF: 0.000309

Gnomad4 NFE AF: 0.000704

Gnomad4 OTH AF: 0.00106

Alfa AF: 0.00793 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:2

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Oct 08, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Megalencephalic leukoencephalopathy with subcortical cysts Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.11
DANN	Benign	0.60

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: rs11568190; hg19: chr22-50502469; COSMIC: COSV61117394;