rs2072873

Variant names:

• chr22-50061538-T-C
• rs2072873
• NM_015166.4:c.*45A>G

Variant summary

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

The NM_001376477.1(MLC1):​c.*45A>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,582,736 control chromosomes in the GnomAD database, including 14,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1772 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12936 hom.)
• Consequence: MLC1 NM_001376477.1 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.53
• Publications: 12 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=-0.93).
• BP6: Variant 22-50061538-T-C is Benign according to our data. Variant chr22-50061538-T-C is described in ClinVar as Benign. ClinVar VariationId is 260572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376477.1. 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.*45A>G		3_prime_UTR	Exon 12 of 12	NP_055981.1
	MLC1	NM_001376477.1		c.*45A>G		splice_region	Exon 11 of 12	NP_001363406.1
	MLC1	NM_001376478.1		c.*45A>G		splice_region	Exon 12 of 13	NP_001363407.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	ENST00000311597.10	TSL:1 MANE Select	c.*45A>G		3_prime_UTR	Exon 12 of 12	ENSP00000310375.6
	MLC1	ENST00000395876.6	TSL:1	c.*45A>G		3_prime_UTR	Exon 12 of 12	ENSP00000379216.2
	MLC1	ENST00000879262.1		c.*45A>G		3_prime_UTR	Exon 13 of 13	ENSP00000549321.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22492 AN: 152122 Hom.: 1764 Cov.: 33

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0979

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.144 AC: 35843 AN: 249526 AF XY: 0.142

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.195

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.133 AC: 189574 AN: 1430494 Hom.: 12936 Cov.: 29 AF XY: 0.133 AC XY: 94650 AN XY: 713724

African (AFR) AF: 0.180 AC: 5890 AN: 32722

American (AMR) AF: 0.160 AC: 7133 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 4479 AN: 25994

East Asian (EAS) AF: 0.197 AC: 7772 AN: 39542

South Asian (SAS) AF: 0.136 AC: 11670 AN: 85712

European-Finnish (FIN) AF: 0.102 AC: 5263 AN: 51410

Middle Eastern (MID) AF: 0.142 AC: 765 AN: 5384

European-Non Finnish (NFE) AF: 0.127 AC: 138356 AN: 1085676

Other (OTH) AF: 0.139 AC: 8246 AN: 59382

GnomAD4 genome AF: 0.148 AC: 22530 AN: 152242 Hom.: 1772 Cov.: 33 AF XY: 0.148 AC XY: 10985 AN XY: 74438

African (AFR) AF: 0.174 AC: 7248 AN: 41538

American (AMR) AF: 0.162 AC: 2472 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 643 AN: 3472

East Asian (EAS) AF: 0.192 AC: 994 AN: 5168

South Asian (SAS) AF: 0.136 AC: 654 AN: 4822

European-Finnish (FIN) AF: 0.0979 AC: 1039 AN: 10618

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

European-Non Finnish (NFE) AF: 0.132 AC: 8974 AN: 68012

Other (OTH) AF: 0.162 AC: 342 AN: 2114

Alfa AF: 0.144 Hom.: 305

Bravo AF: 0.155

Asia WGS AF: 0.173 AC: 604 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.59
DANN	Benign	0.52
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2072873; hg19: chr22-50499967; COSMIC: COSV61119233; COSMIC: COSV61119233;