rs2235349

chr22-50079810-T-C

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: -0.679

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 -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 id 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/exons	MANE	UniProt
MLC1	NM_015166.4	c.423+108A>G		intron_variant		ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.423+108A>G		intron_variant		1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.423+108A>G		intron_variant		1		P1
MLC1	ENST00000442311.1	c.333+108A>G		intron_variant		5

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

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.343

Gnomad4 FIN exome AF: 0.199

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.249

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

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.347

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.261

Alfa AF: 0.223 Hom.: 507

Bravo AF: 0.226

Asia WGS AF: 0.298 AC: 1033 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 15992519, 17210142) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.12
Dann	Benign	0.54

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: rs2235349; hg19: chr22-50518239;