chr22-50070562-T-G

Variant names:

• chr22-50070562-T-G
• rs281875315
• NM_015166.4:c.736A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_015166.4(MLC1):​c.736A>C​(p.Ser246Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,413,004 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.25
• 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), ClinGen, Myriad Women’s Health, G2P, Ambry Genetics
• megalencephalic leukoencephalopathy with subcortical cysts

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 22-50070562-T-G is Pathogenic according to our data. Variant chr22-50070562-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 68796.Status of the report is criteria_provided_single_submitter, 1 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.736A>C	p.Ser246Arg	missense	Exon 9 of 12	NP_055981.1	Q15049-1
	MLC1	NM_001376472.1		c.736A>C	p.Ser246Arg	missense	Exon 8 of 11	NP_001363401.1	Q15049-1
	MLC1	NM_001376473.1		c.736A>C	p.Ser246Arg	missense	Exon 10 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.736A>C	p.Ser246Arg	missense	Exon 9 of 12	ENSP00000310375.6	Q15049-1
	MLC1	ENST00000395876.6	TSL:1	c.736A>C	p.Ser246Arg	missense	Exon 9 of 12	ENSP00000379216.2	Q15049-1
	MLC1	ENST00000879262.1		c.736A>C	p.Ser246Arg	missense	Exon 10 of 13	ENSP00000549321.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1413004 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 697960

African (AFR) AF: 0.00 AC: 0 AN: 32542

American (AMR) AF: 0.00 AC: 0 AN: 37506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25224

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37574

South Asian (SAS) AF: 0.00 AC: 0 AN: 80316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086090

Other (OTH) AF: 0.00 AC: 0 AN: 58558

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.86		Loss of glycosylation at S246 (P = 0.0295)
MVP		0.94
MPC		0.94
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.93
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.060		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: rs281875315; hg19: chr22-50508991;