22-50079918-G-T

Variant names:

• chr22-50079918-G-T
• rs121908343
• NM_015166.4:c.423C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_015166.4(MLC1):​c.423C>A​(p.Asn141Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N141S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MLC1 NM_015166.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001454
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.735
• Publications: 6 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50079919-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4718.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 22-50079918-G-T is Pathogenic according to our data. Variant chr22-50079918-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4717.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	NM_015166.4	MANE Select	c.423C>A	p.Asn141Lys	missense splice_region	Exon 5 of 12	NP_055981.1
	MLC1	NM_001376472.1		c.423C>A	p.Asn141Lys	missense splice_region	Exon 4 of 11	NP_001363401.1
	MLC1	NM_001376473.1		c.423C>A	p.Asn141Lys	missense splice_region	Exon 6 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.423C>A	p.Asn141Lys	missense splice_region	Exon 5 of 12	ENSP00000310375.6
	MLC1	ENST00000395876.6	TSL:1	c.423C>A	p.Asn141Lys	missense splice_region	Exon 5 of 12	ENSP00000379216.2
	MLC1	ENST00000442311.1	TSL:5	c.333C>A	p.Asn111Lys	missense splice_region	Exon 4 of 8	ENSP00000401385.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456550 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724998

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107210

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:1

Mar 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	7.7
DANN	Benign	0.90
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.81	L
PhyloP100		0.73
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Polyphen		0.79	P
Vest4		0.62
MutPred		0.87		Gain of ubiquitination at N141 (P = 0.0247)
MVP		0.62
MPC		0.92
ClinPred		0.99	D
GERP RS		-3.3
Varity_R		0.43
gMVP		0.87
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.13
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: rs121908343; hg19: chr22-50518347;