rs2267193

Variant names:

• chr22-33350540-G-C
• rs2267193
• NM_133642.5:c.1132-12739C>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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]

LARGE1 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy type B6

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133642.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	NM_133642.5	MANE Select	c.1132-12739C>G		intron	N/A	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.1132-12739C>G		intron	N/A	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.1132-12739C>G		intron	N/A	NP_001349880.1	O95461-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.1132-12739C>G		intron	N/A	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.1132-12739C>G		intron	N/A	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.1131+31379C>G		intron	N/A	ENSP00000385223.1	O95461-2

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

African (AFR) AF: 0.0532 AC: 2212 AN: 41550

American (AMR) AF: 0.301 AC: 4598 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1243 AN: 3468

East Asian (EAS) AF: 0.454 AC: 2336 AN: 5148

South Asian (SAS) AF: 0.228 AC: 1099 AN: 4810

European-Finnish (FIN) AF: 0.229 AC: 2432 AN: 10598

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16792 AN: 67982

Other (OTH) AF: 0.248 AC: 525 AN: 2114

Alfa AF: 0.0962 Hom.: 144

Bravo AF: 0.213

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.8
DANN	Benign	0.63
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

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: rs2267193; hg19: chr22-33746526;