22-50059960-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015166.4(MLC1):c.*1623G>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 0.15 in 152,256 control chromosomes in the GnomAD database, including 1,830 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1830 hom., cov: 33)
  • Exomes 𝑓: 0.063 (0 hom.)
• Consequence: MLC1 NM_015166.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0750

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=-0.94).
• BP6: Variant 22-50059960-C-A is Benign according to our data. Variant chr22-50059960-C-A is described in ClinVar as [Benign]. Clinvar id is 342079.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.*1623G>T		3_prime_UTR_variant	12/12	ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.*1623G>T		3_prime_UTR_variant	12/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.*1623G>T		3_prime_UTR_variant	12/12	1		P1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22777 AN: 152058 Hom.: 1822 Cov.: 33

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0975

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.157

GnomAD4 exome AF: 0.0625 AC: 5 AN: 80 Hom.: 0 Cov.: 0 AF XY: 0.0909 AC XY: 4 AN XY: 44

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.0500

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.100

GnomAD4 genome AF: 0.150 AC: 22814 AN: 152176 Hom.: 1830 Cov.: 33 AF XY: 0.149 AC XY: 11098 AN XY: 74398

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.0975

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.165

Alfa AF: 0.0804 Hom.: 115

Bravo AF: 0.156

Asia WGS AF: 0.173 AC: 603 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	-0.94
Cadd	Benign	2.3
Dann	Benign	0.43

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: rs35730155; hg19: chr22-50498389;