chr22-50077414-C-A

Variant names:

• chr22-50077414-C-A
• rs6010260
• NM_015166.4:c.512G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015166.4(MLC1):​c.512G>T​(p.Cys171Phe) variant causes a missense change. The variant allele was found at a frequency of 0.126 in 1,613,234 control chromosomes in the GnomAD database, including 13,601 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (962 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12639 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.82
• Publications: 26 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017397702).
• BP6: Variant 22-50077414-C-A is Benign according to our data. Variant chr22-50077414-C-A is described in ClinVar as Benign. ClinVar VariationId is 21524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

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.512G>T	p.Cys171Phe	missense	Exon 6 of 12	NP_055981.1	Q15049-1
	MLC1	NM_001376472.1		c.512G>T	p.Cys171Phe	missense	Exon 5 of 11	NP_001363401.1	Q15049-1
	MLC1	NM_001376473.1		c.512G>T	p.Cys171Phe	missense	Exon 7 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.512G>T	p.Cys171Phe	missense	Exon 6 of 12	ENSP00000310375.6	Q15049-1
	MLC1	ENST00000395876.6	TSL:1	c.512G>T	p.Cys171Phe	missense	Exon 6 of 12	ENSP00000379216.2	Q15049-1
	MLC1	ENST00000879262.1		c.512G>T	p.Cys171Phe	missense	Exon 7 of 13	ENSP00000549321.1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16089 AN: 152156 Hom.: 961 Cov.: 33

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0596

Gnomad EAS AF: 0.0880

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0723

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.124

GnomAD2 exomes AF: 0.122 AC: 30477 AN: 250474 AF XY: 0.128

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0669

Gnomad EAS exome AF: 0.0877

Gnomad FIN exome AF: 0.0801

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.128 AC: 186526 AN: 1460960 Hom.: 12639 Cov.: 33 AF XY: 0.131 AC XY: 95087 AN XY: 726798

African (AFR) AF: 0.0684 AC: 2290 AN: 33474

American (AMR) AF: 0.128 AC: 5704 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0640 AC: 1672 AN: 26134

East Asian (EAS) AF: 0.0985 AC: 3911 AN: 39688

South Asian (SAS) AF: 0.222 AC: 19161 AN: 86192

European-Finnish (FIN) AF: 0.0840 AC: 4467 AN: 53172

Middle Eastern (MID) AF: 0.136 AC: 782 AN: 5740

European-Non Finnish (NFE) AF: 0.127 AC: 141046 AN: 1111486

Other (OTH) AF: 0.124 AC: 7493 AN: 60366

GnomAD4 genome AF: 0.106 AC: 16094 AN: 152274 Hom.: 962 Cov.: 33 AF XY: 0.106 AC XY: 7897 AN XY: 74466

African (AFR) AF: 0.0678 AC: 2817 AN: 41552

American (AMR) AF: 0.154 AC: 2354 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0596 AC: 207 AN: 3472

East Asian (EAS) AF: 0.0882 AC: 457 AN: 5184

South Asian (SAS) AF: 0.226 AC: 1089 AN: 4826

European-Finnish (FIN) AF: 0.0723 AC: 768 AN: 10620

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8016 AN: 67998

Other (OTH) AF: 0.122 AC: 258 AN: 2114

Alfa AF: 0.112 Hom.: 1003

Bravo AF: 0.108

TwinsUK AF: 0.129 AC: 479

ALSPAC AF: 0.128 AC: 492

ESP6500AA AF: 0.0708 AC: 312

ESP6500EA AF: 0.118 AC: 1019

ExAC AF: 0.123 AC: 14963

Asia WGS AF: 0.146 AC: 506 AN: 3478

EpiCase AF: 0.117

EpiControl AF: 0.123

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Megalencephalic leukoencephalopathy with subcortical cysts 1 (2)
-	-	2	not specified (2)
-	-	1	Megalencephalic leukoencephalopathy with subcortical cysts (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.8
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-11	D
REVEL	Benign	0.23
Sift	Benign	0.034	D
Sift4G	Benign	0.14	T
Polyphen		0.18	B
Vest4		0.13
MPC		0.82
ClinPred		0.065	T
GERP RS		3.3
Varity_R		0.69
gMVP		0.82
Mutation Taster		=97/3	polymorphism (auto)

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: rs6010260; hg19: chr22-50515843; COSMIC: COSV61115765; COSMIC: COSV61115765;