rs137919

Variant names:

• chr22-50061535-T-C
• rs137919
• NM_015166.4:c.*48A>G

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.*48A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,574,564 control chromosomes in the GnomAD database, including 71,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5259 hom., cov: 33)
  • Exomes 𝑓: 0.30 (66483 hom.)
• Consequence: MLC1 NM_015166.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.84
• Publications: 11 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 22-50061535-T-C is Benign according to our data. Variant chr22-50061535-T-C is described in ClinVar as Benign. ClinVar VariationId is 262456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.*48A>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.*48A>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.*48A>G		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000379216.2
MLC1	ENST00000483836.1	n.539A>G		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37318 AN: 152078 Hom.: 5257 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.273

GnomAD2 exomes AF: 0.299 AC: 74608 AN: 249194 AF XY: 0.308

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.337

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.301 AC: 428558 AN: 1422368 Hom.: 66483 Cov.: 27 AF XY: 0.305 AC XY: 216789 AN XY: 710018

African (AFR) AF: 0.106 AC: 3465 AN: 32594

American (AMR) AF: 0.341 AC: 15212 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 5517 AN: 25934

East Asian (EAS) AF: 0.357 AC: 14080 AN: 39472

South Asian (SAS) AF: 0.415 AC: 35532 AN: 85546

European-Finnish (FIN) AF: 0.255 AC: 13021 AN: 51038

Middle Eastern (MID) AF: 0.288 AC: 1527 AN: 5308

European-Non Finnish (NFE) AF: 0.300 AC: 323095 AN: 1078680

Other (OTH) AF: 0.289 AC: 17109 AN: 59122

GnomAD4 genome AF: 0.245 AC: 37331 AN: 152196 Hom.: 5259 Cov.: 33 AF XY: 0.247 AC XY: 18411 AN XY: 74414

African (AFR) AF: 0.111 AC: 4617 AN: 41544

American (AMR) AF: 0.322 AC: 4929 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 703 AN: 3472

East Asian (EAS) AF: 0.345 AC: 1780 AN: 5162

South Asian (SAS) AF: 0.423 AC: 2041 AN: 4824

European-Finnish (FIN) AF: 0.239 AC: 2530 AN: 10604

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19741 AN: 67982

Other (OTH) AF: 0.271 AC: 572 AN: 2114

Alfa AF: 0.276 Hom.: 6873

Bravo AF: 0.244

Asia WGS AF: 0.362 AC: 1257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:2

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	0.20
DANN	Benign	0.38
PhyloP100		-3.8
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: rs137919; hg19: chr22-50499964; COSMIC: COSV61117386; COSMIC: COSV61117386;