22-33823952-A-G

Variant names:

• chr22-33823952-A-G
• rs2267296
• NM_133642.5:c.-82-62394T>C

Variant summary

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

The NM_133642.5(LARGE1):​c.-82-62394T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 151,888 control chromosomes in the GnomAD database, including 19,493 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 0.50 (19493 hom., cov: 31)
• Consequence: LARGE1 NM_133642.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	NM_133642.5	c.-82-62394T>C		intron_variant	Intron 1 of 14	ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8	c.-82-62394T>C		intron_variant	Intron 1 of 14	5	NM_133642.5	ENSP00000380549.2

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76503 AN: 151770 Hom.: 19478 Cov.: 31

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.493

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

GnomAD4 genome AF: 0.504 AC: 76550 AN: 151888 Hom.: 19493 Cov.: 31 AF XY: 0.504 AC XY: 37431 AN XY: 74206

African (AFR) AF: 0.523 AC: 21650 AN: 41372

American (AMR) AF: 0.377 AC: 5763 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1759 AN: 3470

East Asian (EAS) AF: 0.595 AC: 3063 AN: 5152

South Asian (SAS) AF: 0.647 AC: 3111 AN: 4808

European-Finnish (FIN) AF: 0.534 AC: 5640 AN: 10552

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33806 AN: 67948

Other (OTH) AF: 0.498 AC: 1052 AN: 2114

Alfa AF: 0.495 Hom.: 76181

Bravo AF: 0.487

Asia WGS AF: 0.607 AC: 2111 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.4
DANN	Benign	0.47
PhyloP100		1.7
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: rs2267296; hg19: chr22-34219939;