rs755271052

Positions:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_015166.4(MLC1):​c.895-1G>C variant causes a splice acceptor 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 (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLC1 NM_015166.4 splice_acceptor
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.138

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1446208 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 id is 371564.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4	c.895-1G>C		splice_acceptor_variant		ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.895-1G>C		splice_acceptor_variant		1	NM_015166.4	ENSP00000310375	P1
MLC1	ENST00000395876.6	c.895-1G>C		splice_acceptor_variant		1		ENSP00000379216	P1
MLC1	ENST00000483836.1	n.252-1G>C		splice_acceptor_variant, non_coding_transcript_variant		2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Oct 26, 2016

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.97	D;D;D;D;D;D
GERP RS		1.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs755271052; hg19: chr22-50502628;