22-50059620-G-C

Position:

• chr22-50059620-G-C

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.*1963C>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 0.0416 in 152,412 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.042 (187 hom., cov: 33)
  • Exomes 𝑓: 0.068 (0 hom.)
• Consequence: MLC1 NM_015166.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.233

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=-0.83).
• BP6: Variant 22-50059620-G-C is Benign according to our data. Variant chr22-50059620-G-C is described in ClinVar as [Benign]. Clinvar id is 342075.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.*1963C>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.*1963C>G		3_prime_UTR_variant	12/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.*1963C>G		3_prime_UTR_variant	12/12	1		P1

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6335 AN: 152162 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.00999

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0545

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0536

GnomAD4 exome AF: 0.0682 AC: 9 AN: 132 Hom.: 0 Cov.: 0 AF XY: 0.0385 AC XY: 3 AN XY: 78

Gnomad4 EAS exome AF: 0.0741

Gnomad4 NFE exome AF: 0.0455

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0416 AC: 6331 AN: 152280 Hom.: 187 Cov.: 33 AF XY: 0.0421 AC XY: 3135 AN XY: 74452

Gnomad4 AFR AF: 0.00996

Gnomad4 AMR AF: 0.0544

Gnomad4 ASJ AF: 0.0683

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.0699

Gnomad4 NFE AF: 0.0562

Gnomad4 OTH AF: 0.0531

Alfa AF: 0.0145 Hom.: 5

Bravo AF: 0.0405

Asia WGS AF: 0.0130 AC: 46 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	-0.83
CADD	Benign	3.8
DANN	Benign	0.72

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: rs41283487; hg19: chr22-50498049;