chr22-50068590-G-A

Variant names:

• chr22-50068590-G-A
• rs11568179
• NM_015166.4:c.772-35C>T

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.772-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,604,718 control chromosomes in the GnomAD database, including 18,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1278 hom., cov: 31)
  • Exomes 𝑓: 0.15 (17221 hom.)
• Consequence: MLC1 NM_015166.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.44
• Publications: 7 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=-0.93).
• BP6: Variant 22-50068590-G-A is Benign according to our data. Variant chr22-50068590-G-A is described in ClinVar as Benign. ClinVar VariationId is 262460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.772-35C>T		intron_variant	Intron 9 of 11	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.772-35C>T		intron_variant	Intron 9 of 11	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.772-35C>T		intron_variant	Intron 9 of 11	1		ENSP00000379216.2
MLC1	ENST00000483836.1	n.129-35C>T		intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18576 AN: 151808 Hom.: 1278 Cov.: 31

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.0975

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.0855

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.138 AC: 34372 AN: 248190 AF XY: 0.145

Gnomad AFR exome AF: 0.0760

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.0879

Gnomad EAS exome AF: 0.0967

Gnomad FIN exome AF: 0.0948

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.149 AC: 216808 AN: 1452792 Hom.: 17221 Cov.: 35 AF XY: 0.152 AC XY: 109646 AN XY: 722780

African (AFR) AF: 0.0729 AC: 2407 AN: 33004

American (AMR) AF: 0.138 AC: 6116 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.0839 AC: 2176 AN: 25932

East Asian (EAS) AF: 0.101 AC: 3980 AN: 39366

South Asian (SAS) AF: 0.222 AC: 19079 AN: 85938

European-Finnish (FIN) AF: 0.0981 AC: 5070 AN: 51676

Middle Eastern (MID) AF: 0.149 AC: 795 AN: 5330

European-Non Finnish (NFE) AF: 0.152 AC: 168689 AN: 1107310

Other (OTH) AF: 0.142 AC: 8496 AN: 59766

GnomAD4 genome AF: 0.122 AC: 18582 AN: 151926 Hom.: 1278 Cov.: 31 AF XY: 0.123 AC XY: 9117 AN XY: 74222

African (AFR) AF: 0.0750 AC: 3110 AN: 41474

American (AMR) AF: 0.175 AC: 2668 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3470

East Asian (EAS) AF: 0.0979 AC: 504 AN: 5148

South Asian (SAS) AF: 0.230 AC: 1099 AN: 4782

European-Finnish (FIN) AF: 0.0855 AC: 904 AN: 10578

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.141 AC: 9574 AN: 67882

Other (OTH) AF: 0.146 AC: 309 AN: 2112

Alfa AF: 0.0800 Hom.: 129

Bravo AF: 0.124

Asia WGS AF: 0.154 AC: 534 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.93
CADD	Benign	0.46
DANN	Benign	0.48
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11568179; hg19: chr22-50507019;