rs41283489

Variant names:

• chr22-50059819-C-A
• rs41283489
• NM_015166.4:c.*1764G>T

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.*1764G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,392 control chromosomes in the GnomAD database, including 1,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1695 hom., cov: 33)
  • Exomes 𝑓: 0.16 (1 hom.)
• Consequence: MLC1 NM_015166.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.156

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=-0.84).
• BP6: Variant 22-50059819-C-A is Benign according to our data. Variant chr22-50059819-C-A is described in ClinVar as [Benign]. Clinvar id is 342078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.*1764G>T		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	c.*1764G>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876	c.*1764G>T		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000379216.2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19837 AN: 152194 Hom.: 1696 Cov.: 33

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.0970

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.124

GnomAD4 exome AF: 0.163 AC: 13 AN: 80 Hom.: 1 Cov.: 0 AF XY: 0.182 AC XY: 8 AN XY: 44

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.152

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.130 AC: 19823 AN: 152312 Hom.: 1695 Cov.: 33 AF XY: 0.128 AC XY: 9554 AN XY: 74480

Gnomad4 AFR AF: 0.0326

Gnomad4 AMR AF: 0.0968

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.00598

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.122

Alfa AF: 0.149 Hom.: 294

Bravo AF: 0.115

Asia WGS AF: 0.0650 AC: 226 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:1

Jan 12, 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:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.4
DANN	Benign	0.78

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: rs41283489; hg19: chr22-50498248;