22-50074276-G-A

Variant names:

• chr22-50074276-G-A
• rs41302601
• NM_015166.4:c.654C>T

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.654C>T​(p.Asn218Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: MLC1 NM_015166.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0900
• Publications: 14 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 22-50074276-G-A is Benign according to our data. Variant chr22-50074276-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1143678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.09 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.654C>T	p.Asn218Asn	synonymous_variant	Exon 8 of 12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.654C>T	p.Asn218Asn	synonymous_variant	Exon 8 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.654C>T	p.Asn218Asn	synonymous_variant	Exon 8 of 12	1		ENSP00000379216.2
MLC1	ENST00000442311.1	c.564C>T	p.Asn188Asn	synonymous_variant	Exon 7 of 8	5		ENSP00000401385.1
MLC1	ENST00000470008.1	n.134C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000479 AC: 12 AN: 250566 AF XY: 0.0000516

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727180

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1111990

Other (OTH) AF: 0.0000662 AC: 4 AN: 60392

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74508

African (AFR) AF: 0.0000481 AC: 2 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00000202 Hom.: 6

Bravo AF: 0.0000567

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MLC1: BP4, BP7 -

Feb 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.33
DANN	Benign	0.80
PhyloP100		0.090
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41302601; hg19: chr22-50512705;