chr22-50074188-C-T

Variant names:

• chr22-50074188-C-T
• rs2038048
• NM_015166.4:c.714+28G>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.714+28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,576,360 control chromosomes in the GnomAD database, including 151,498 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11766 hom., cov: 32)
  • Exomes 𝑓: 0.44 (139732 hom.)
• Consequence: MLC1 NM_015166.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.10
• Publications: 8 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=-0.88).
• BP6: Variant 22-50074188-C-T is Benign according to our data. Variant chr22-50074188-C-T is described in ClinVar as Benign. ClinVar VariationId is 262458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015166.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	NM_015166.4	MANE Select	c.714+28G>A		intron	N/A	NP_055981.1
	MLC1	NM_001376472.1		c.714+28G>A		intron	N/A	NP_001363401.1
	MLC1	NM_001376473.1		c.714+28G>A		intron	N/A	NP_001363402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	ENST00000311597.10	TSL:1 MANE Select	c.714+28G>A		intron	N/A	ENSP00000310375.6
	MLC1	ENST00000395876.6	TSL:1	c.714+28G>A		intron	N/A	ENSP00000379216.2
	MLC1	ENST00000879262.1		c.714+28G>A		intron	N/A	ENSP00000549321.1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57185 AN: 151874 Hom.: 11752 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.367

GnomAD2 exomes AF: 0.405 AC: 94078 AN: 232462 AF XY: 0.404

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.476

Gnomad ASJ exome AF: 0.385

Gnomad EAS exome AF: 0.209

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.438 AC: 623499 AN: 1424368 Hom.: 139732 Cov.: 26 AF XY: 0.435 AC XY: 308385 AN XY: 709598

African (AFR) AF: 0.209 AC: 6867 AN: 32796

American (AMR) AF: 0.472 AC: 20238 AN: 42876

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 9848 AN: 25676

East Asian (EAS) AF: 0.205 AC: 8050 AN: 39206

South Asian (SAS) AF: 0.338 AC: 28549 AN: 84352

European-Finnish (FIN) AF: 0.448 AC: 23328 AN: 52070

Middle Eastern (MID) AF: 0.343 AC: 1950 AN: 5690

European-Non Finnish (NFE) AF: 0.462 AC: 500276 AN: 1082616

Other (OTH) AF: 0.413 AC: 24393 AN: 59086

GnomAD4 genome AF: 0.377 AC: 57228 AN: 151992 Hom.: 11766 Cov.: 32 AF XY: 0.377 AC XY: 27979 AN XY: 74304

African (AFR) AF: 0.217 AC: 8999 AN: 41464

American (AMR) AF: 0.452 AC: 6909 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1385 AN: 3466

East Asian (EAS) AF: 0.208 AC: 1072 AN: 5162

South Asian (SAS) AF: 0.334 AC: 1603 AN: 4802

European-Finnish (FIN) AF: 0.447 AC: 4730 AN: 10570

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31202 AN: 67928

Other (OTH) AF: 0.371 AC: 783 AN: 2112

Alfa AF: 0.411 Hom.: 2467

Bravo AF: 0.370

Asia WGS AF: 0.295 AC: 1027 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Megalencephalic leukoencephalopathy with subcortical cysts 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.84
PhyloP100		-1.1
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: rs2038048; hg19: chr22-50512617; COSMIC: COSV61116963; COSMIC: COSV61116963;