rs11568188

Variant names:

• chr22-50064062-T-C
• rs11568188
• NM_015166.4:c.1031A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-50064062-T-C
• chr22-50064062-T-G

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.1031A>G​(p.Asn344Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,480,250 control chromosomes in the GnomAD database, including 15,810 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N344N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.099 (1081 hom., cov: 32)
  • Exomes 𝑓: 0.12 (14729 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.631
• Publications: 19 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=0.0020861626).
• BP6: Variant 22-50064062-T-C is Benign according to our data. Variant chr22-50064062-T-C is described in ClinVar as Benign. ClinVar VariationId is 21521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 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.1031A>G	p.Asn344Ser	missense	Exon 11 of 12	NP_055981.1	Q15049-1
	MLC1	NM_001376472.1		c.1031A>G	p.Asn344Ser	missense	Exon 10 of 11	NP_001363401.1	Q15049-1
	MLC1	NM_001376473.1		c.1031A>G	p.Asn344Ser	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.1031A>G	p.Asn344Ser	missense	Exon 11 of 12	ENSP00000310375.6	Q15049-1
	MLC1	ENST00000395876.6	TSL:1	c.1031A>G	p.Asn344Ser	missense	Exon 11 of 12	ENSP00000379216.2	Q15049-1
	MLC1	ENST00000879262.1		c.1031A>G	p.Asn344Ser	missense	Exon 12 of 13	ENSP00000549321.1

Frequencies

GnomAD3 genomes AF: 0.0991 AC: 12277 AN: 123832 Hom.: 1081 Cov.: 32

Gnomad AFR AF: 0.0575

Gnomad AMI AF: 0.0916

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.0612

Gnomad EAS AF: 0.0826

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0642

Gnomad MID AF: 0.0985

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.113 AC: 26164 AN: 232170 AF XY: 0.119

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0769

Gnomad EAS exome AF: 0.0790

Gnomad FIN exome AF: 0.0562

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.120 AC: 163080 AN: 1356324 Hom.: 14729 Cov.: 37 AF XY: 0.123 AC XY: 83100 AN XY: 675326

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

African (AFR) AF: 0.0581 AC: 1879 AN: 32366

American (AMR) AF: 0.113 AC: 4772 AN: 42184

Ashkenazi Jewish (ASJ) AF: 0.0705 AC: 1787 AN: 25338

East Asian (EAS) AF: 0.0892 AC: 3434 AN: 38504

South Asian (SAS) AF: 0.196 AC: 15762 AN: 80562

European-Finnish (FIN) AF: 0.0722 AC: 3334 AN: 46152

Middle Eastern (MID) AF: 0.108 AC: 536 AN: 4944

European-Non Finnish (NFE) AF: 0.121 AC: 124838 AN: 1029484

Other (OTH) AF: 0.119 AC: 6738 AN: 56790

⚠️ 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 AF: 0.0991 AC: 12285 AN: 123926 Hom.: 1081 Cov.: 32 AF XY: 0.100 AC XY: 6042 AN XY: 60204

African (AFR) AF: 0.0578 AC: 1974 AN: 34150

American (AMR) AF: 0.157 AC: 1898 AN: 12094

Ashkenazi Jewish (ASJ) AF: 0.0612 AC: 183 AN: 2988

East Asian (EAS) AF: 0.0829 AC: 345 AN: 4160

South Asian (SAS) AF: 0.200 AC: 702 AN: 3516

European-Finnish (FIN) AF: 0.0642 AC: 552 AN: 8594

Middle Eastern (MID) AF: 0.0868 AC: 21 AN: 242

European-Non Finnish (NFE) AF: 0.114 AC: 6335 AN: 55728

Other (OTH) AF: 0.121 AC: 207 AN: 1712

Alfa AF: 0.141 Hom.: 1499

Bravo AF: 0.124

TwinsUK AF: 0.131 AC: 487

ALSPAC AF: 0.136 AC: 525

ESP6500AA AF: 0.0663 AC: 292

ESP6500EA AF: 0.127 AC: 1094

ExAC AF: 0.0816 AC: 9819

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.3
DANN	Benign	0.37
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.63
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.18
Sift	Benign	0.83	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.039
MPC		0.20
ClinPred		0.00075	T
GERP RS		1.7
Varity_R		0.025
gMVP		0.075
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs11568188; hg19: chr22-50502491; COSMIC: COSV61115728;