rs2413187

Variant names:

• chr22-33468831-A-G
• rs2413187
• NM_133642.5:c.788-36566T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000397394.8(LARGE1):​c.788-36566T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 152,002 control chromosomes in the GnomAD database, including 2,909 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 0.19 (2909 hom., cov: 32)
• Consequence: LARGE1 ENST00000397394.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.322
• Publications: 4 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 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397394.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	NM_133642.5	MANE Select	c.788-36566T>C		intron	N/A	NP_598397.1
	LARGE1	NM_001362949.2		c.788-36566T>C		intron	N/A	NP_001349878.1
	LARGE1	NM_001362951.2		c.788-36566T>C		intron	N/A	NP_001349880.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.788-36566T>C		intron	N/A	ENSP00000380549.2
	LARGE1	ENST00000354992.7	TSL:1	c.788-36566T>C		intron	N/A	ENSP00000347088.2
	LARGE1	ENST00000402320.6	TSL:1	c.788-36566T>C		intron	N/A	ENSP00000385223.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29425 AN: 151884 Hom.: 2907 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.201

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

GnomAD4 genome AF: 0.194 AC: 29439 AN: 152002 Hom.: 2909 Cov.: 32 AF XY: 0.192 AC XY: 14234 AN XY: 74298

African (AFR) AF: 0.220 AC: 9126 AN: 41422

American (AMR) AF: 0.234 AC: 3580 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3470

East Asian (EAS) AF: 0.133 AC: 686 AN: 5168

South Asian (SAS) AF: 0.245 AC: 1176 AN: 4806

European-Finnish (FIN) AF: 0.128 AC: 1351 AN: 10568

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

European-Non Finnish (NFE) AF: 0.184 AC: 12488 AN: 67978

Other (OTH) AF: 0.200 AC: 423 AN: 2114

Alfa AF: 0.190 Hom.: 5105

Bravo AF: 0.202

Asia WGS AF: 0.191 AC: 667 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.4
DANN	Benign	0.53
PhyloP100		0.32
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: rs2413187; hg19: chr22-33864817;