22-50064161-A-G

Variant names:

• chr22-50064161-A-G
• rs141225099
• NM_015166.4:c.932T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015166.4(MLC1):​c.932T>C​(p.Val311Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V311E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17353672).

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.932T>C	p.Val311Ala	missense	Exon 11 of 12	NP_055981.1
	MLC1	NM_001376472.1		c.932T>C	p.Val311Ala	missense	Exon 10 of 11	NP_001363401.1
	MLC1	NM_001376473.1		c.932T>C	p.Val311Ala	missense	Exon 12 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.932T>C	p.Val311Ala	missense	Exon 11 of 12	ENSP00000310375.6
	MLC1	ENST00000395876.6	TSL:1	c.932T>C	p.Val311Ala	missense	Exon 11 of 12	ENSP00000379216.2
	MLC1	ENST00000483836.1	TSL:2	n.289T>C		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453872 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 723486

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46506

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111602

Other (OTH) AF: 0.00 AC: 0 AN: 60250

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.023
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.19
Sift	Benign	0.059	T
Sift4G	Benign	0.16	T
Polyphen		0.010	B
Vest4		0.16
MutPred		0.45		Loss of stability (P = 0.0179)
MVP		0.51
MPC		0.31
ClinPred		0.084	T
GERP RS		2.9
Varity_R		0.058
gMVP		0.22
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs141225099; hg19: chr22-50502590;