rs137919

Positions:

• chr22-50061535-T-C

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: -3.84

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
MLC1	NM_015166.4	c.*48A>G		3_prime_UTR_variant	12/12	ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.*48A>G		3_prime_UTR_variant	12/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.*48A>G		3_prime_UTR_variant	12/12	1		P1
MLC1	ENST00000483836.1	n.539A>G		non_coding_transcript_exon_variant	5/5	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

GnomAD3 exomes AF: 0.299 AC: 74608 AN: 249194 Hom.: 11928 AF XY: 0.308 AC XY: 41563 AN XY: 135012

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 SAS exome AF: 0.414

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

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.341

Gnomad4 ASJ exome AF: 0.213

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.415

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.289

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

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.345

Gnomad4 SAS AF: 0.423

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.290

Gnomad4 OTH AF: 0.271

Alfa AF: 0.282 Hom.: 5564

Bravo AF: 0.244

Asia WGS AF: 0.362 AC: 1257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.20
DANN	Benign	0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs137919; hg19: chr22-50499964; COSMIC: COSV61117386; COSMIC: COSV61117386;