chr22-50076844-G-A

Variant names:

• chr22-50076844-G-A
• rs6010165
• NM_015166.4:c.594C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000311597.10(MLC1):​c.594C>T​(p.Tyr198Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,612,906 control chromosomes in the GnomAD database, including 13,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1077 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12783 hom.)
• Consequence: MLC1 ENST00000311597.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.110
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 22-50076844-G-A is Benign according to our data. Variant chr22-50076844-G-A is described in ClinVar as Benign. ClinVar VariationId is 129614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000311597.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	NM_015166.4	MANE Select	c.594C>T	p.Tyr198Tyr	synonymous	Exon 7 of 12	NP_055981.1
	MLC1	NM_001376472.1		c.594C>T	p.Tyr198Tyr	synonymous	Exon 6 of 11	NP_001363401.1
	MLC1	NM_001376473.1		c.594C>T	p.Tyr198Tyr	synonymous	Exon 8 of 13	NP_001363402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	ENST00000311597.10	TSL:1 MANE Select	c.594C>T	p.Tyr198Tyr	synonymous	Exon 7 of 12	ENSP00000310375.6
	MLC1	ENST00000395876.6	TSL:1	c.594C>T	p.Tyr198Tyr	synonymous	Exon 7 of 12	ENSP00000379216.2
	MLC1	ENST00000442311.1	TSL:5	c.504C>T	p.Tyr168Tyr	synonymous	Exon 6 of 8	ENSP00000401385.1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17631 AN: 152086 Hom.: 1073 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.0891

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0724

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.124 AC: 31262 AN: 251116 AF XY: 0.131

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.0669

Gnomad EAS exome AF: 0.0878

Gnomad FIN exome AF: 0.0801

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.129 AC: 187899 AN: 1460702 Hom.: 12783 Cov.: 32 AF XY: 0.132 AC XY: 95684 AN XY: 726718

African (AFR) AF: 0.102 AC: 3426 AN: 33454

American (AMR) AF: 0.130 AC: 5796 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 1670 AN: 26130

East Asian (EAS) AF: 0.0988 AC: 3920 AN: 39692

South Asian (SAS) AF: 0.222 AC: 19183 AN: 86232

European-Finnish (FIN) AF: 0.0842 AC: 4494 AN: 53352

Middle Eastern (MID) AF: 0.139 AC: 802 AN: 5758

European-Non Finnish (NFE) AF: 0.127 AC: 140968 AN: 1111032

Other (OTH) AF: 0.127 AC: 7640 AN: 60342

GnomAD4 genome AF: 0.116 AC: 17648 AN: 152204 Hom.: 1077 Cov.: 33 AF XY: 0.116 AC XY: 8648 AN XY: 74436

African (AFR) AF: 0.104 AC: 4309 AN: 41532

American (AMR) AF: 0.157 AC: 2392 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 207 AN: 3470

East Asian (EAS) AF: 0.0893 AC: 462 AN: 5176

South Asian (SAS) AF: 0.225 AC: 1086 AN: 4826

European-Finnish (FIN) AF: 0.0724 AC: 768 AN: 10606

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.118 AC: 8020 AN: 67996

Other (OTH) AF: 0.129 AC: 273 AN: 2112

Alfa AF: 0.119 Hom.: 1827

Bravo AF: 0.119

Asia WGS AF: 0.147 AC: 510 AN: 3478

EpiCase AF: 0.117

EpiControl AF: 0.123

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Megalencephalic leukoencephalopathy with subcortical cysts 1 (2)
-	-	1	Megalencephalic leukoencephalopathy with subcortical cysts (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.54
DANN	Benign	0.24
PhyloP100		-0.11
Mutation Taster		=99/1	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: rs6010165; hg19: chr22-50515273; COSMIC: COSV61117553; COSMIC: COSV61117553;