22-50080294-A-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.321+50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.933 in 1,562,152 control chromosomes in the GnomAD database, including 680,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68863 hom., cov: 33)
  • Exomes 𝑓: 0.93 (611747 hom.)
• Consequence: MLC1 NM_015166.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.59

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 (BayesDel_noAF=-0.94).
• BP6: Variant 22-50080294-A-G is Benign according to our data. Variant chr22-50080294-A-G is described in ClinVar as [Benign]. Clinvar id is 260573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.321+50T>C		intron_variant		ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.321+50T>C		intron_variant		1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.321+50T>C		intron_variant		1		P1
MLC1	ENST00000442311.1	c.231+50T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.950 AC: 144630 AN: 152220 Hom.: 68798 Cov.: 33

Gnomad AFR AF: 0.986

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.952

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.982

Gnomad FIN AF: 0.974

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.921

Gnomad OTH AF: 0.936

GnomAD3 exomes AF: 0.949 AC: 192215 AN: 202522 Hom.: 91330 AF XY: 0.949 AC XY: 103036 AN XY: 108614

Gnomad AFR exome AF: 0.989

Gnomad AMR exome AF: 0.957

Gnomad ASJ exome AF: 0.899

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.983

Gnomad FIN exome AF: 0.973

Gnomad NFE exome AF: 0.924

Gnomad OTH exome AF: 0.931

GnomAD4 exome AF: 0.931 AC: 1312951 AN: 1409814 Hom.: 611747 Cov.: 29 AF XY: 0.932 AC XY: 652305 AN XY: 699760

Gnomad4 AFR exome AF: 0.989

Gnomad4 AMR exome AF: 0.955

Gnomad4 ASJ exome AF: 0.898

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.982

Gnomad4 FIN exome AF: 0.971

Gnomad4 NFE exome AF: 0.921

Gnomad4 OTH exome AF: 0.936

GnomAD4 genome AF: 0.950 AC: 144754 AN: 152338 Hom.: 68863 Cov.: 33 AF XY: 0.953 AC XY: 71021 AN XY: 74496

Gnomad4 AFR AF: 0.986

Gnomad4 AMR AF: 0.952

Gnomad4 ASJ AF: 0.910

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.982

Gnomad4 FIN AF: 0.974

Gnomad4 NFE AF: 0.921

Gnomad4 OTH AF: 0.937

Alfa AF: 0.930 Hom.: 12231

Bravo AF: 0.950

Asia WGS AF: 0.992 AC: 3449 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.51
Dann	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79301; hg19: chr22-50518723;