rs2267193

Positions:

• chr22-33350540-G-C
• chr22-33350540-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_133642.5(LARGE1):​c.1132-12739C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 152,128 control chromosomes in the GnomAD database, including 4,100 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4100 hom., cov: 32)
• Consequence: LARGE1 NM_133642.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.518

Genes affected

LARGE1 (HGNC:6511): (LARGE xylosyl- and glucuronyltransferase 1) This gene encodes a member of the N-acetylglucosaminyltransferase gene family. It encodes a glycosyltransferase which participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. It may also be involved in the addition of a repeated disaccharide unit. The protein encoded by this gene is the glycotransferase that adds the final xylose and glucuronic acid to alpha-dystroglycan and thereby allows alpha-dystroglycan to bind ligands including laminin 211 and neurexin. Mutations in this gene cause several forms of congenital muscular dystrophy characterized by cognitive disability and abnormal glycosylation of alpha-dystroglycan. Alternative splicing of this gene results in multiple transcript variants that encode the same protein. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARGE1	NM_133642.5	c.1132-12739C>G		intron_variant		ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8	c.1132-12739C>G		intron_variant		5	NM_133642.5	ENSP00000380549	P1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31598 AN: 152010 Hom.: 4096 Cov.: 32

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.248

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.208 AC: 31609 AN: 152128 Hom.: 4100 Cov.: 32 AF XY: 0.210 AC XY: 15611 AN XY: 74386

Gnomad4 AFR AF: 0.0532

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.229

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.248

Alfa AF: 0.0962 Hom.: 144

Bravo AF: 0.213

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.8
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs2267193; hg19: chr22-33746526;