22-50060249-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015166.4(MLC1):c.*1334G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 152,366 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLC1 NM_015166.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.708

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 22-50060249-C-T is Benign according to our data. Variant chr22-50060249-C-T is described in ClinVar as [Benign]. Clinvar id is 342083.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0127 (1940/152366) while in subpopulation EAS AF= 0.0414 (215/5188). AF 95% confidence interval is 0.0369. There are 34 homozygotes in gnomad4. There are 1155 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.*1334G>A		3_prime_UTR_variant	12/12	ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.*1334G>A		3_prime_UTR_variant	12/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.*1334G>A		3_prime_UTR_variant	12/12	1		P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1941 AN: 152248 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.0415

Gnomad SAS AF: 0.0401

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00779

Gnomad OTH AF: 0.00716

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 166 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 92

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0127 AC: 1940 AN: 152366 Hom.: 34 Cov.: 33 AF XY: 0.0155 AC XY: 1155 AN XY: 74512

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.0414

Gnomad4 SAS AF: 0.0399

Gnomad4 FIN AF: 0.0465

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.0116 Hom.: 3

Bravo AF: 0.0106

Asia WGS AF: 0.0510 AC: 175 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.74
Dann	Benign	0.65

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: rs2294382; hg19: chr22-50498678;