rs755271052

Variant names:

• chr22-50064199-C-G
• rs755271052
• NM_015166.4:c.895-1G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-50064199-C-G
• chr22-50064199-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_015166.4(MLC1):​c.895-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLC1 NM_015166.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.138
• Publications: 2 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: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• megalencephalic leukoencephalopathy with subcortical cysts

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.14550264 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of 37, new splice context is: gctgctgctgctgctgctAGtgc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50064199-C-G is Pathogenic according to our data. Variant chr22-50064199-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 371564.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	NM_015166.4	MANE Select	c.895-1G>C		splice_acceptor intron	N/A	NP_055981.1	Q15049-1
	MLC1	NM_001376472.1		c.895-1G>C		splice_acceptor intron	N/A	NP_001363401.1	Q15049-1
	MLC1	NM_001376473.1		c.895-1G>C		splice_acceptor intron	N/A	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.895-1G>C		splice_acceptor intron	N/A	ENSP00000310375.6	Q15049-1
	MLC1	ENST00000395876.6	TSL:1	c.895-1G>C		splice_acceptor intron	N/A	ENSP00000379216.2	Q15049-1
	MLC1	ENST00000879262.1		c.895-1G>C		splice_acceptor intron	N/A	ENSP00000549321.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441184 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 716818

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 43648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 84946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108000

Other (OTH) AF: 0.00 AC: 0 AN: 59962

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Megalencephalic leukoencephalopathy with subcortical cysts 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Benign	0.53
Eigen	Benign	0.17
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.049	N
PhyloP100		0.14
GERP RS		1.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -38
DS_AL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs755271052; hg19: chr22-50502628;