rs6010164

Positions:

chr22-50076841-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000311597.10(MLC1):c.597A>G(p.Ser199=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,612,712 control chromosomes in the GnomAD database, including 13,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1076 hom., cov: 33)

Exomes 𝑓: 0.13 ( 12807 hom. )

Consequence

MLC1
ENST00000311597.10 splice_region, synonymous

Scores

Splicing: ADA: 0.00005492

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.43

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 22-50076841-T-C is Benign according to our data. Variant chr22-50076841-T-C is described in ClinVar as [Benign]. Clinvar id is 129615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50076841-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.43 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	Protein	UniProt
MLC1	NM_015166.4 linkuse as main transcript	c.597A>G	p.Ser199=	splice_region_variant, synonymous_variant	7/12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10 linkuse as main transcript	c.597A>G	p.Ser199=	splice_region_variant, synonymous_variant	7/12	1	NM_015166.4	ENSP00000310375	P1	Q15049-1
MLC1	ENST00000395876.6 linkuse as main transcript	c.597A>G	p.Ser199=	splice_region_variant, synonymous_variant	7/12	1		ENSP00000379216	P1	Q15049-1
MLC1	ENST00000442311.1 linkuse as main transcript	c.507A>G	p.Ser169=	splice_region_variant, synonymous_variant	6/8	5		ENSP00000401385

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17630

AN:

152046

Hom.:

1072

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.157

Gnomad ASJ

AF:

0.0597

Gnomad EAS

AF:

0.0889

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.0725

Gnomad MID

AF:

0.115

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.131

GnomAD3 exomes

AF:

0.125

AC:

31277

AN:

251120

Hom.:

2159

AF XY:

0.131

AC XY:

17733

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.0669

Gnomad EAS exome

AF:

0.0879

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:

188041

AN:

1460548

Hom.:

12807

Cov.:

AF XY:

0.132

AC XY:

95766

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.102

Gnomad4 AMR exome

AF:

0.130

Gnomad4 ASJ exome

AF:

0.0639

Gnomad4 EAS exome

AF:

0.0990

Gnomad4 SAS exome

AF:

0.222

Gnomad4 FIN exome

AF:

0.0843

Gnomad4 NFE exome

AF:

0.127

Gnomad4 OTH exome

AF:

0.127

GnomAD4 genome

AF:

0.116

AC:

17647

AN:

152164

Hom.:

1076

Cov.:

AF XY:

0.116

AC XY:

8646

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.104

Gnomad4 AMR

AF:

0.157

Gnomad4 ASJ

AF:

0.0597

Gnomad4 EAS

AF:

0.0891

Gnomad4 SAS

AF:

0.225

Gnomad4 FIN

AF:

0.0725

Gnomad4 NFE

AF:

0.118

Gnomad4 OTH

AF:

0.129

Alfa

AF:

0.118

Hom.:

1946

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

LINK: link

Submissions by phenotype

not provided

Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

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	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. -

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

-0.78

CADD

Benign

0.024

DANN

Benign

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over