rs80358245

Variant names:

• chr22-50080387-G-A
• rs80358245
• NM_015166.4:c.278C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-50080387-G-A
• chr22-50080387-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PP3_Moderate PP5_Very_Strong

The NM_015166.4(MLC1):​c.278C>T​(p.Ser93Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000023 in 1,605,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001578024: Experimental studies have shown that this missense change affects MLC1 function (PMID:18757878, 22006981)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S93S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.19
• Publications: 21 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), ClinGen, Myriad Women’s Health, G2P, Ambry Genetics
• megalencephalic leukoencephalopathy with subcortical cysts

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001578024: Experimental studies have shown that this missense change affects MLC1 function (PMID: 18757878, 22006981).; SCV003845178: Experimental evidence demonstrated the variant affects protein function (Duarri_2008, Ridder_2014).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_015166.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 22-50080387-G-A is Pathogenic according to our data. Variant chr22-50080387-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015166.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	NM_015166.4	MANE Select	c.278C>T	p.Ser93Leu	missense	Exon 4 of 12	NP_055981.1	Q15049-1
	MLC1	NM_001376472.1		c.278C>T	p.Ser93Leu	missense	Exon 3 of 11	NP_001363401.1	Q15049-1
	MLC1	NM_001376473.1		c.278C>T	p.Ser93Leu	missense	Exon 5 of 13	NP_001363402.1	Q15049-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	ENST00000311597.10	TSL:1 MANE Select	c.278C>T	p.Ser93Leu	missense	Exon 4 of 12	ENSP00000310375.6	Q15049-1
	MLC1	ENST00000395876.6	TSL:1	c.278C>T	p.Ser93Leu	missense	Exon 4 of 12	ENSP00000379216.2	Q15049-1
	MLC1	ENST00000879262.1		c.278C>T	p.Ser93Leu	missense	Exon 5 of 13	ENSP00000549321.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000171 AC: 4 AN: 234558 AF XY: 0.0000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000491

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000241 AC: 35 AN: 1452924 Hom.: 0 Cov.: 33 AF XY: 0.0000277 AC XY: 20 AN XY: 721916

African (AFR) AF: 0.00 AC: 0 AN: 33182

American (AMR) AF: 0.0000229 AC: 1 AN: 43762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.000357 AC: 14 AN: 39186

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84400

European-Finnish (FIN) AF: 0.000133 AC: 7 AN: 52708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000722 AC: 8 AN: 1107906

Other (OTH) AF: 0.0000666 AC: 4 AN: 60060

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74506

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Megalencephalic leukoencephalopathy with subcortical cysts 1 (4)
2	-	-	not provided (2)
1	-	-	Megalencephalic leukoencephalopathy with subcortical cysts (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.2
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.80		Gain of sheet (P = 0.0221)
MVP		0.91
MPC		0.77
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.55
gMVP		0.88
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80358245; hg19: chr22-50518816; COSMIC: COSV61119371;