rs139336504

Variant names:

• chr22-50064085-C-A
• rs139336504
• NM_015166.4:c.1008G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-50064085-C-A
• chr22-50064085-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_015166.4(MLC1):​c.1008G>T​(p.Gln336His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,609,726 control chromosomes in the GnomAD database, including 8 homozygotes. 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. Q336R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (6 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.375
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4064023).
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.1008G>T	p.Gln336His	missense	Exon 11 of 12	NP_055981.1	Q15049-1
	MLC1	NM_001376472.1		c.1008G>T	p.Gln336His	missense	Exon 10 of 11	NP_001363401.1	Q15049-1
	MLC1	NM_001376473.1		c.1008G>T	p.Gln336His	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.1008G>T	p.Gln336His	missense	Exon 11 of 12	ENSP00000310375.6	Q15049-1
	MLC1	ENST00000395876.6	TSL:1	c.1008G>T	p.Gln336His	missense	Exon 11 of 12	ENSP00000379216.2	Q15049-1
	MLC1	ENST00000879262.1		c.1008G>T	p.Gln336His	missense	Exon 12 of 13	ENSP00000549321.1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151604 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.000579

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000190 AC: 47 AN: 247902 AF XY: 0.000178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000102

Gnomad NFE exome AF: 0.000320

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000147 AC: 214 AN: 1458122 Hom.: 6 Cov.: 39 AF XY: 0.000135 AC XY: 98 AN XY: 725594

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.000291 AC: 13 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.000219 AC: 11 AN: 50138

Middle Eastern (MID) AF: 0.000533 AC: 3 AN: 5628

European-Non Finnish (NFE) AF: 0.000151 AC: 168 AN: 1111854

Other (OTH) AF: 0.000282 AC: 17 AN: 60326

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151604 Hom.: 2 Cov.: 34 AF XY: 0.000203 AC XY: 15 AN XY: 74032

African (AFR) AF: 0.0000485 AC: 2 AN: 41238

American (AMR) AF: 0.000329 AC: 5 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.000579 AC: 2 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67852

Other (OTH) AF: 0.00144 AC: 3 AN: 2084

Alfa AF: 0.000254 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.38
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.27
Sift	Benign	0.16	T
Sift4G	Benign	0.27	T
Polyphen		0.99	D
Vest4		0.43
MutPred		0.23		Gain of methylation at R334 (P = 0.0454)
MVP		0.81
MPC		0.86
ClinPred		0.076	T
GERP RS		1.9
Varity_R		0.14
gMVP		0.25
Mutation Taster		=92/8	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: rs139336504; hg19: chr22-50502514;