chr22-50064110-C-T

Variant names:

• chr22-50064110-C-T
• rs145376667
• NM_015166.4:c.983G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015166.4(MLC1):​c.983G>A​(p.Arg328His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000392 in 1,608,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R328S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.0150
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P, Ambry Genetics
• megalencephalic leukoencephalopathy with subcortical cysts

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04232034).

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.983G>A	p.Arg328His	missense	Exon 11 of 12	NP_055981.1	Q15049-1
	MLC1	NM_001376472.1		c.983G>A	p.Arg328His	missense	Exon 10 of 11	NP_001363401.1	Q15049-1
	MLC1	NM_001376473.1		c.983G>A	p.Arg328His	missense	Exon 12 of 13	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.983G>A	p.Arg328His	missense	Exon 11 of 12	ENSP00000310375.6	Q15049-1
	MLC1	ENST00000395876.6	TSL:1	c.983G>A	p.Arg328His	missense	Exon 11 of 12	ENSP00000379216.2	Q15049-1
	MLC1	ENST00000879262.1		c.983G>A	p.Arg328His	missense	Exon 12 of 13	ENSP00000549321.1

Frequencies

GnomAD3 genomes AF: 0.000220 AC: 33 AN: 150058 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000682

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000673

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000650

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000484 AC: 12 AN: 248066 AF XY: 0.0000519

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1458434 Hom.: 0 Cov.: 39 AF XY: 0.0000207 AC XY: 15 AN XY: 725732

African (AFR) AF: 0.000149 AC: 5 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111866

Other (OTH) AF: 0.0000166 AC: 1 AN: 60342

GnomAD4 genome AF: 0.000220 AC: 33 AN: 150178 Hom.: 0 Cov.: 34 AF XY: 0.000232 AC XY: 17 AN XY: 73304

African (AFR) AF: 0.000680 AC: 28 AN: 41178

American (AMR) AF: 0.0000672 AC: 1 AN: 14876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.000651 AC: 3 AN: 4610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67288

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000618 Hom.: 0

Bravo AF: 0.000257

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Megalencephalic leukoencephalopathy with subcortical cysts 1 (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.015
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.11	N
REVEL	Uncertain	0.51
Sift	Benign	0.27	T
Sift4G	Benign	0.27	T
Polyphen		0.0030	B
Vest4		0.17
MVP		0.63
MPC		0.40
ClinPred		0.016	T
GERP RS		1.8
Varity_R		0.032
gMVP		0.19
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs145376667; hg19: chr22-50502539;