rs141225099

chr22-50064161-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015166.4(MLC1):c.932T>A(p.Val311Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,606,162 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (14 hom., cov: 34)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0230

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_015166.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.01006338).
• BP6: Variant 22-50064161-A-T is Benign according to our data. Variant chr22-50064161-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 262462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50064161-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00579 (881/152290) while in subpopulation AFR AF= 0.0201 (834/41556). AF 95% confidence interval is 0.0189. There are 14 homozygotes in gnomad4. There are 422 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.932T>A	p.Val311Glu	missense_variant	11/12	ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.932T>A	p.Val311Glu	missense_variant	11/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.932T>A	p.Val311Glu	missense_variant	11/12	1		P1
MLC1	ENST00000483836.1	n.289T>A		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.00579 AC: 881 AN: 152172 Hom.: 13 Cov.: 34

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00149 AC: 359 AN: 240508 Hom.: 5 AF XY: 0.000996 AC XY: 131 AN XY: 131584

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000536 AC: 779 AN: 1453872 Hom.: 7 Cov.: 39 AF XY: 0.000419 AC XY: 303 AN XY: 723486

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00579 AC: 881 AN: 152290 Hom.: 14 Cov.: 34 AF XY: 0.00567 AC XY: 422 AN XY: 74470

Gnomad4 AFR AF: 0.0201

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00659

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00192 AC: 232

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	14
Dann	Benign	0.95
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.16	N
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.22
Sift	Benign	0.23	T;T
Sift4G	Benign	0.097	T;T
Polyphen		0.0	B;B
Vest4		0.26
MVP		0.56
MPC		0.44
ClinPred		0.0053	T
GERP RS		2.9
Varity_R		0.18
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs141225099; hg19: chr22-50502590;