rs137930

Variant names:

• chr22-50085004-T-C
• rs137930
• NM_015166.4:c.-59-43A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001376472.1(MLC1):​c.-102A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,541,730 control chromosomes in the GnomAD database, including 87,940 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (6325 hom., cov: 33)
  • Exomes 𝑓: 0.33 (81615 hom.)
• Consequence: MLC1 NM_001376472.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.243
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376472.1. 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.-59-43A>G		intron	N/A	NP_055981.1
	MLC1	NM_001376472.1		c.-102A>G		5_prime_UTR	Exon 1 of 11	NP_001363401.1
	MLC1	NM_001376477.1		c.-102A>G		5_prime_UTR	Exon 1 of 12	NP_001363406.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	ENST00000311597.10	TSL:1 MANE Select	c.-59-43A>G		intron	N/A	ENSP00000310375.6
	MLC1	ENST00000395876.6	TSL:1	c.-59-43A>G		intron	N/A	ENSP00000379216.2
	MLC1	ENST00000879274.1		c.-102A>G		5_prime_UTR	Exon 1 of 11	ENSP00000549333.1

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39717 AN: 152150 Hom.: 6329 Cov.: 33

Gnomad AFR AF: 0.0966

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0265

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.334 AC: 463440 AN: 1389462 Hom.: 81615 Cov.: 29 AF XY: 0.331 AC XY: 227626 AN XY: 687068

African (AFR) AF: 0.0845 AC: 2702 AN: 31976

American (AMR) AF: 0.252 AC: 9249 AN: 36710

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5755 AN: 25174

East Asian (EAS) AF: 0.0213 AC: 790 AN: 37174

South Asian (SAS) AF: 0.252 AC: 20279 AN: 80626

European-Finnish (FIN) AF: 0.362 AC: 12794 AN: 35354

Middle Eastern (MID) AF: 0.229 AC: 1065 AN: 4660

European-Non Finnish (NFE) AF: 0.364 AC: 393363 AN: 1079742

Other (OTH) AF: 0.301 AC: 17443 AN: 58046

GnomAD4 genome AF: 0.261 AC: 39715 AN: 152268 Hom.: 6325 Cov.: 33 AF XY: 0.260 AC XY: 19391 AN XY: 74440

African (AFR) AF: 0.0965 AC: 4013 AN: 41566

American (AMR) AF: 0.309 AC: 4719 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 796 AN: 3468

East Asian (EAS) AF: 0.0266 AC: 138 AN: 5194

South Asian (SAS) AF: 0.248 AC: 1200 AN: 4830

European-Finnish (FIN) AF: 0.362 AC: 3830 AN: 10592

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24080 AN: 68012

Other (OTH) AF: 0.232 AC: 490 AN: 2112

Alfa AF: 0.277 Hom.: 1407

Bravo AF: 0.246

Asia WGS AF: 0.154 AC: 537 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.65
PhyloP100		-0.24
PromoterAI		0.013	Neutral
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: rs137930; hg19: chr22-50523433; COSMIC: COSV107329768; COSMIC: COSV107329768;