rs2076137

Variant names:

• chr22-50077337-C-T
• rs2076137
• NM_015166.4:c.525+64G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015166.4(MLC1):​c.525+64G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,447,098 control chromosomes in the GnomAD database, including 16,018 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1731 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14287 hom.)
• Consequence: MLC1 NM_015166.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0210
• Publications: 10 publications found

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]

MLC1 Gene-Disease associations (from GenCC):

• megalencephalic leukoencephalopathy with subcortical cysts 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Myriad Women’s Health
• megalencephalic leukoencephalopathy with subcortical cysts

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-50077337-C-T is Benign according to our data. Variant chr22-50077337-C-T is described in ClinVar as Benign. ClinVar VariationId is 1165670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.525+64G>A		intron_variant	Intron 6 of 11	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.525+64G>A		intron_variant	Intron 6 of 11	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.525+64G>A		intron_variant	Intron 6 of 11	1		ENSP00000379216.2
MLC1	ENST00000442311.1	c.435+64G>A		intron_variant	Intron 5 of 7	5		ENSP00000401385.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21732 AN: 152084 Hom.: 1715 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.155

GnomAD4 exome AF: 0.145 AC: 187527 AN: 1294894 Hom.: 14287 AF XY: 0.145 AC XY: 94198 AN XY: 650146

African (AFR) AF: 0.113 AC: 3410 AN: 30192

American (AMR) AF: 0.283 AC: 11744 AN: 41540

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4473 AN: 24946

East Asian (EAS) AF: 0.201 AC: 7682 AN: 38248

South Asian (SAS) AF: 0.148 AC: 11942 AN: 80666

European-Finnish (FIN) AF: 0.121 AC: 6047 AN: 49922

Middle Eastern (MID) AF: 0.144 AC: 764 AN: 5310

European-Non Finnish (NFE) AF: 0.138 AC: 133452 AN: 969256

Other (OTH) AF: 0.146 AC: 8013 AN: 54814

GnomAD4 genome AF: 0.143 AC: 21769 AN: 152204 Hom.: 1731 Cov.: 33 AF XY: 0.143 AC XY: 10672 AN XY: 74428

African (AFR) AF: 0.112 AC: 4634 AN: 41526

American (AMR) AF: 0.212 AC: 3249 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 678 AN: 3472

East Asian (EAS) AF: 0.196 AC: 1013 AN: 5162

South Asian (SAS) AF: 0.152 AC: 731 AN: 4822

European-Finnish (FIN) AF: 0.115 AC: 1220 AN: 10622

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9690 AN: 67988

Other (OTH) AF: 0.162 AC: 343 AN: 2116

Alfa AF: 0.148 Hom.: 218

Bravo AF: 0.151

Asia WGS AF: 0.182 AC: 633 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15992519, 17210142) -

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:1

Jun 10, 2021

Genome-Nilou Lab

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	-0.90
CADD	Benign	6.2
DANN	Benign	0.61
PhyloP100		0.021
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2076137; hg19: chr22-50515766; COSMIC: COSV61115881; COSMIC: COSV61115881;