chr22-50064221-G-A

Variant names:

• chr22-50064221-G-A
• rs11568184
• NM_015166.4:c.895-23C>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.895-23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,574,750 control chromosomes in the GnomAD database, including 17,706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1260 hom., cov: 34)
  • Exomes 𝑓: 0.15 (16446 hom.)
• Consequence: MLC1 NM_015166.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.733
• Publications: 5 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=-0.82).
• BP6: Variant 22-50064221-G-A is Benign according to our data. Variant chr22-50064221-G-A is described in ClinVar as Benign. ClinVar VariationId is 262461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.895-23C>T		intron_variant	Intron 10 of 11	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.895-23C>T		intron_variant	Intron 10 of 11	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.895-23C>T		intron_variant	Intron 10 of 11	1		ENSP00000379216.2
MLC1	ENST00000483836.1	n.252-23C>T		intron_variant	Intron 3 of 4	2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18565 AN: 152094 Hom.: 1259 Cov.: 34

Gnomad AFR AF: 0.0748

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0775

Gnomad EAS AF: 0.0975

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.0857

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.126 AC: 24253 AN: 192352 AF XY: 0.132

Gnomad AFR exome AF: 0.0639

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.0830

Gnomad EAS exome AF: 0.0854

Gnomad FIN exome AF: 0.0778

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.149 AC: 211760 AN: 1422536 Hom.: 16446 Cov.: 38 AF XY: 0.151 AC XY: 106589 AN XY: 706068

African (AFR) AF: 0.0723 AC: 2399 AN: 33170

American (AMR) AF: 0.133 AC: 5437 AN: 40970

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 2135 AN: 25542

East Asian (EAS) AF: 0.100 AC: 3893 AN: 38830

South Asian (SAS) AF: 0.218 AC: 18143 AN: 83210

European-Finnish (FIN) AF: 0.0956 AC: 3555 AN: 37182

Middle Eastern (MID) AF: 0.144 AC: 788 AN: 5474

European-Non Finnish (NFE) AF: 0.152 AC: 166964 AN: 1098836

Other (OTH) AF: 0.142 AC: 8446 AN: 59322

GnomAD4 genome AF: 0.122 AC: 18572 AN: 152214 Hom.: 1260 Cov.: 34 AF XY: 0.123 AC XY: 9117 AN XY: 74418

African (AFR) AF: 0.0749 AC: 3112 AN: 41554

American (AMR) AF: 0.174 AC: 2658 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0775 AC: 269 AN: 3470

East Asian (EAS) AF: 0.0979 AC: 506 AN: 5168

South Asian (SAS) AF: 0.229 AC: 1104 AN: 4824

European-Finnish (FIN) AF: 0.0857 AC: 910 AN: 10616

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9563 AN: 67964

Other (OTH) AF: 0.146 AC: 309 AN: 2114

Alfa AF: 0.120 Hom.: 210

Bravo AF: 0.124

Asia WGS AF: 0.155 AC: 538 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	-0.82
CADD	Benign	6.7
DANN	Benign	0.90
PhyloP100		0.73
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: rs11568184; hg19: chr22-50502650; COSMIC: COSV107329767;