rs2235349

Variant names:

• chr22-50079810-T-C
• rs2235349
• NM_015166.4:c.423+108A>G

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.423+108A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 853,096 control chromosomes in the GnomAD database, including 27,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3956 hom., cov: 31)
  • Exomes 𝑓: 0.26 (23730 hom.)
• Consequence: MLC1 NM_015166.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.679
• Publications: 6 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=-0.87).
• BP6: Variant 22-50079810-T-C is Benign according to our data. Variant chr22-50079810-T-C is described in ClinVar as Benign. ClinVar VariationId is 1165671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.423+108A>G		intron_variant	Intron 5 of 11	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.423+108A>G		intron_variant	Intron 5 of 11	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.423+108A>G		intron_variant	Intron 5 of 11	1		ENSP00000379216.2
MLC1	ENST00000442311.1	c.333+108A>G		intron_variant	Intron 4 of 7	5		ENSP00000401385.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33357 AN: 152026 Hom.: 3936 Cov.: 31

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.254

GnomAD4 exome AF: 0.256 AC: 179145 AN: 700952 Hom.: 23730 AF XY: 0.259 AC XY: 97439 AN XY: 375502

African (AFR) AF: 0.155 AC: 2965 AN: 19070

American (AMR) AF: 0.357 AC: 15494 AN: 43392

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 4969 AN: 21452

East Asian (EAS) AF: 0.286 AC: 10295 AN: 36056

South Asian (SAS) AF: 0.343 AC: 24268 AN: 70788

European-Finnish (FIN) AF: 0.199 AC: 9294 AN: 46768

Middle Eastern (MID) AF: 0.269 AC: 1103 AN: 4098

European-Non Finnish (NFE) AF: 0.240 AC: 101927 AN: 423926

Other (OTH) AF: 0.249 AC: 8830 AN: 35402

GnomAD4 genome AF: 0.219 AC: 33395 AN: 152144 Hom.: 3956 Cov.: 31 AF XY: 0.220 AC XY: 16392 AN XY: 74398

African (AFR) AF: 0.149 AC: 6187 AN: 41502

American (AMR) AF: 0.295 AC: 4504 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 844 AN: 3468

East Asian (EAS) AF: 0.269 AC: 1393 AN: 5176

South Asian (SAS) AF: 0.347 AC: 1678 AN: 4832

European-Finnish (FIN) AF: 0.182 AC: 1927 AN: 10584

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16022 AN: 67992

Other (OTH) AF: 0.261 AC: 551 AN: 2108

Alfa AF: 0.229 Hom.: 1216

Bravo AF: 0.226

Asia WGS AF: 0.298 AC: 1033 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15992519, 17210142) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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	-0.87
CADD	Benign	0.12
DANN	Benign	0.54
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

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: rs2235349; hg19: chr22-50518239;