22-50059747-C-T

Position:

• chr22-50059747-C-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.*1836G>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 0.0972 in 152,446 control chromosomes in the GnomAD database, including 871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (871 hom., cov: 33)
  • Exomes 𝑓: 0.074 (0 hom.)
• Consequence: MLC1 NM_015166.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.83

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=-1.02).
• BP6: Variant 22-50059747-C-T is Benign according to our data. Variant chr22-50059747-C-T is described in ClinVar as [Benign]. Clinvar id is 342076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4	c.*1836G>A		3_prime_UTR_variant	12/12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.*1836G>A		3_prime_UTR_variant	12/12	1	NM_015166.4	ENSP00000310375	P1
MLC1	ENST00000395876.6	c.*1836G>A		3_prime_UTR_variant	12/12	1		ENSP00000379216	P1

Frequencies

GnomAD3 genomes AF: 0.0974 AC: 14811 AN: 152124 Hom.: 871 Cov.: 33

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0814

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.0563

Gnomad FIN AF: 0.0977

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.0735 AC: 15 AN: 204 Hom.: 0 Cov.: 0 AF XY: 0.0809 AC XY: 11 AN XY: 136

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.0700

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.0526

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.0973 AC: 14808 AN: 152242 Hom.: 871 Cov.: 33 AF XY: 0.0947 AC XY: 7049 AN XY: 74426

Gnomad4 AFR AF: 0.0532

Gnomad4 AMR AF: 0.0813

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.0194

Gnomad4 SAS AF: 0.0561

Gnomad4 FIN AF: 0.0977

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.109

Alfa AF: 0.121 Hom.: 314

Bravo AF: 0.0942

Asia WGS AF: 0.0400 AC: 139 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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.12
DANN	Benign	0.62

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: rs11703598; hg19: chr22-50498176;