rs2072873

Variant names:

• chr22-50061538-T-C
• rs2072873
• NM_015166.4:c.*45A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001376477.1(MLC1):​c.*45A>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,582,736 control chromosomes in the GnomAD database, including 14,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1772 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12936 hom.)
• Consequence: MLC1 NM_001376477.1 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.53

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=-0.93).
• BP6: Variant 22-50061538-T-C is Benign according to our data. Variant chr22-50061538-T-C is described in ClinVar as [Benign]. Clinvar id is 260572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.*45A>G		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.*45A>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876	c.*45A>G		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000379216.2
MLC1	ENST00000483836.1	n.536A>G		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22492 AN: 152122 Hom.: 1764 Cov.: 33

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0979

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.154

GnomAD3 exomes AF: 0.144 AC: 35843 AN: 249526 Hom.: 2669 AF XY: 0.142 AC XY: 19235 AN XY: 135182

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.133 AC: 189574 AN: 1430494 Hom.: 12936 Cov.: 29 AF XY: 0.133 AC XY: 94650 AN XY: 713724

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.148 AC: 22530 AN: 152242 Hom.: 1772 Cov.: 33 AF XY: 0.148 AC XY: 10985 AN XY: 74438

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.0979

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.162

Alfa AF: 0.144 Hom.: 305

Bravo AF: 0.155

Asia WGS AF: 0.173 AC: 604 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:2

Jan 13, 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. -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.59
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2072873; hg19: chr22-50499967; COSMIC: COSV61119233; COSMIC: COSV61119233;