rs121908344

Positions:

• chr22-50079919-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_015166.4(MLC1):​c.422A>G​(p.Asn141Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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. N141K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLC1 NM_015166.4 missense, splice_region
• Scores: Splicing: ADA: 0.5942
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.17

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50079918-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 4717.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 22-50079919-T-C is Pathogenic according to our data. Variant chr22-50079919-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4718.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-50079919-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.422A>G	p.Asn141Ser	missense_variant, splice_region_variant	5/12	ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.422A>G	p.Asn141Ser	missense_variant, splice_region_variant	5/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.422A>G	p.Asn141Ser	missense_variant, splice_region_variant	5/12	1		P1
MLC1	ENST00000442311.1	c.332A>G	p.Asn111Ser	missense_variant, splice_region_variant	4/8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	.;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.81	L;L;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.55
Sift	Benign	0.093	T;T;T
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.59	P;P;.
Vest4		0.81
MutPred		0.83		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;
MVP		0.85
MPC		0.66
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.23
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908344; hg19: chr22-50518348;