22-50077379-C-T

Variant names:

• chr22-50077379-C-T
• rs2072874
• NM_015166.4:c.525+22G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015166.4(MLC1):​c.525+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,602,054 control chromosomes in the GnomAD database, including 17,733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1735 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15998 hom.)
• Consequence: MLC1 NM_015166.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.03
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• megalencephalic leukoencephalopathy with subcortical cysts 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Myriad Women’s Health
• megalencephalic leukoencephalopathy with subcortical cysts

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-50077379-C-T is Benign according to our data. Variant chr22-50077379-C-T is described in ClinVar as Benign. ClinVar VariationId is 260574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.525+22G>A		intron_variant	Intron 6 of 11	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.525+22G>A		intron_variant	Intron 6 of 11	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.525+22G>A		intron_variant	Intron 6 of 11	1		ENSP00000379216.2
MLC1	ENST00000442311.1	c.435+22G>A		intron_variant	Intron 5 of 7	5		ENSP00000401385.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21757 AN: 152114 Hom.: 1719 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.167 AC: 41386 AN: 247908 AF XY: 0.163

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.145 AC: 209850 AN: 1449822 Hom.: 15998 Cov.: 30 AF XY: 0.145 AC XY: 104432 AN XY: 721788

African (AFR) AF: 0.114 AC: 3796 AN: 33244

American (AMR) AF: 0.285 AC: 12685 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4671 AN: 26054

East Asian (EAS) AF: 0.201 AC: 7971 AN: 39616

South Asian (SAS) AF: 0.148 AC: 12702 AN: 85750

European-Finnish (FIN) AF: 0.121 AC: 6414 AN: 52894

Middle Eastern (MID) AF: 0.148 AC: 846 AN: 5712

European-Non Finnish (NFE) AF: 0.138 AC: 152034 AN: 1102068

Other (OTH) AF: 0.146 AC: 8731 AN: 59980

GnomAD4 genome AF: 0.143 AC: 21793 AN: 152232 Hom.: 1735 Cov.: 33 AF XY: 0.143 AC XY: 10672 AN XY: 74440

African (AFR) AF: 0.112 AC: 4635 AN: 41544

American (AMR) AF: 0.213 AC: 3261 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 679 AN: 3470

East Asian (EAS) AF: 0.197 AC: 1021 AN: 5172

South Asian (SAS) AF: 0.151 AC: 727 AN: 4818

European-Finnish (FIN) AF: 0.115 AC: 1220 AN: 10622

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9694 AN: 67990

Other (OTH) AF: 0.163 AC: 345 AN: 2116

Alfa AF: 0.150 Hom.: 339

Bravo AF: 0.151

Asia WGS AF: 0.183 AC: 635 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.17
DANN	Benign	0.69
PhyloP100		-4.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2072874; hg19: chr22-50515808; COSMIC: COSV61115889; COSMIC: COSV61115889;