chr22-50064040-A-G

Variant names:

• chr22-50064040-A-G
• rs11568190
• NM_015166.4:c.1053T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_015166.4(MLC1):​c.1053T>C​(p.Ala351Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A351A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00060 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLC1 NM_015166.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -6.10
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 22-50064040-A-G is Benign according to our data. Variant chr22-50064040-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.1 with no splicing effect.

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.1053T>C	p.Ala351Ala	synonymous	Exon 11 of 12	NP_055981.1	Q15049-1
	MLC1	NM_001376472.1		c.1053T>C	p.Ala351Ala	synonymous	Exon 10 of 11	NP_001363401.1	Q15049-1
	MLC1	NM_001376473.1		c.1053T>C	p.Ala351Ala	synonymous	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.1053T>C	p.Ala351Ala	synonymous	Exon 11 of 12	ENSP00000310375.6	Q15049-1
	MLC1	ENST00000395876.6	TSL:1	c.1053T>C	p.Ala351Ala	synonymous	Exon 11 of 12	ENSP00000379216.2	Q15049-1
	MLC1	ENST00000879262.1		c.1053T>C	p.Ala351Ala	synonymous	Exon 12 of 13	ENSP00000549321.1

Frequencies

GnomAD3 genomes AF: 0.000602 AC: 83 AN: 137870 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000234

Gnomad AMI AF: 0.00377

Gnomad AMR AF: 0.000957

Gnomad ASJ AF: 0.000305

Gnomad EAS AF: 0.000631

Gnomad SAS AF: 0.00153

Gnomad FIN AF: 0.000309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000703

Gnomad OTH AF: 0.00107

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000391 AC: 527 AN: 1348570 Hom.: 7 Cov.: 36 AF XY: 0.000430 AC XY: 288 AN XY: 670410

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

African (AFR) AF: 0.000154 AC: 5 AN: 32432

American (AMR) AF: 0.000667 AC: 28 AN: 41956

Ashkenazi Jewish (ASJ) AF: 0.000198 AC: 5 AN: 25260

East Asian (EAS) AF: 0.000260 AC: 10 AN: 38492

South Asian (SAS) AF: 0.000777 AC: 60 AN: 77172

European-Finnish (FIN) AF: 0.000715 AC: 31 AN: 43340

Middle Eastern (MID) AF: 0.000430 AC: 2 AN: 4646

European-Non Finnish (NFE) AF: 0.000357 AC: 367 AN: 1028756

Other (OTH) AF: 0.000336 AC: 19 AN: 56516

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000601 AC: 83 AN: 137996 Hom.: 2 Cov.: 33 AF XY: 0.000594 AC XY: 40 AN XY: 67378

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

African (AFR) AF: 0.000233 AC: 9 AN: 38632

American (AMR) AF: 0.000955 AC: 13 AN: 13608

Ashkenazi Jewish (ASJ) AF: 0.000305 AC: 1 AN: 3284

East Asian (EAS) AF: 0.000632 AC: 3 AN: 4744

South Asian (SAS) AF: 0.00153 AC: 6 AN: 3926

European-Finnish (FIN) AF: 0.000309 AC: 3 AN: 9722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000704 AC: 43 AN: 61118

Other (OTH) AF: 0.00106 AC: 2 AN: 1890

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000188116), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00793 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.11
DANN	Benign	0.60
PhyloP100		-6.1
Mutation Taster		=100/0	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: rs11568190; hg19: chr22-50502469; COSMIC: COSV61117394;