rs11568185

Variant names:

• chr22-50064207-G-A
• rs11568185
• NM_015166.4:c.895-9C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-50064207-G-A
• chr22-50064207-G-C

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.895-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,585,140 control chromosomes in the GnomAD database, including 17,829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1267 hom., cov: 34)
  • Exomes 𝑓: 0.15 (16562 hom.)
• Consequence: MLC1 NM_015166.4 intron
• Scores: Splicing: ADA: 0.00002558
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.83
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-50064207-G-A is Benign according to our data. Variant chr22-50064207-G-A is described in ClinVar as Benign. ClinVar VariationId is 129616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 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.895-9C>T		intron	N/A	NP_055981.1
	MLC1	NM_001376472.1		c.895-9C>T		intron	N/A	NP_001363401.1
	MLC1	NM_001376473.1		c.895-9C>T		intron	N/A	NP_001363402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLC1	ENST00000311597.10	TSL:1 MANE Select	c.895-9C>T		intron	N/A	ENSP00000310375.6
	MLC1	ENST00000395876.6	TSL:1	c.895-9C>T		intron	N/A	ENSP00000379216.2
	MLC1	ENST00000879262.1		c.895-9C>T		intron	N/A	ENSP00000549321.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18569 AN: 152096 Hom.: 1266 Cov.: 34

Gnomad AFR AF: 0.0745

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.0980

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.0857

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.127 AC: 26554 AN: 208606 AF XY: 0.134

Gnomad AFR exome AF: 0.0646

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.0835

Gnomad EAS exome AF: 0.0870

Gnomad FIN exome AF: 0.0791

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.149 AC: 213518 AN: 1432924 Hom.: 16562 Cov.: 38 AF XY: 0.151 AC XY: 107668 AN XY: 712024

African (AFR) AF: 0.0726 AC: 2419 AN: 33320

American (AMR) AF: 0.132 AC: 5620 AN: 42574

Ashkenazi Jewish (ASJ) AF: 0.0837 AC: 2151 AN: 25712

East Asian (EAS) AF: 0.101 AC: 3961 AN: 39230

South Asian (SAS) AF: 0.219 AC: 18403 AN: 84164

European-Finnish (FIN) AF: 0.0950 AC: 3677 AN: 38690

Middle Eastern (MID) AF: 0.146 AC: 807 AN: 5538

European-Non Finnish (NFE) AF: 0.152 AC: 167967 AN: 1103978

Other (OTH) AF: 0.143 AC: 8513 AN: 59718

GnomAD4 genome AF: 0.122 AC: 18576 AN: 152216 Hom.: 1267 Cov.: 34 AF XY: 0.123 AC XY: 9121 AN XY: 74410

African (AFR) AF: 0.0747 AC: 3102 AN: 41548

American (AMR) AF: 0.174 AC: 2658 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3470

East Asian (EAS) AF: 0.0984 AC: 509 AN: 5172

South Asian (SAS) AF: 0.229 AC: 1107 AN: 4830

European-Finnish (FIN) AF: 0.0857 AC: 909 AN: 10604

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

European-Non Finnish (NFE) AF: 0.141 AC: 9570 AN: 67974

Other (OTH) AF: 0.146 AC: 309 AN: 2114

Alfa AF: 0.121 Hom.: 237

Bravo AF: 0.124

Asia WGS AF: 0.156 AC: 539 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.10
DANN	Benign	0.56
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0020
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: rs11568185; hg19: chr22-50502636; COSMIC: COSV107329766;