22-33283291-C-T

Variant names:

• chr22-33283291-C-T
• rs74550830
• NM_133642.5:c.1788G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_133642.5(LARGE1):​c.1788G>A​(p.Ala596Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,614,108 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A596A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (16 hom.)
• Consequence: LARGE1 NM_133642.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -5.16
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 22-33283291-C-T is Benign according to our data. Variant chr22-33283291-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167250.
• BP7: Synonymous conserved (PhyloP=-5.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00218 (332/152222) while in subpopulation NFE AF = 0.00322 (219/68010). AF 95% confidence interval is 0.00287. There are 2 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1788G>A	p.Ala596Ala	synonymous	Exon 13 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.1788G>A	p.Ala596Ala	synonymous	Exon 14 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.1788G>A	p.Ala596Ala	synonymous	Exon 13 of 15	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.1788G>A	p.Ala596Ala	synonymous	Exon 13 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.1788G>A	p.Ala596Ala	synonymous	Exon 14 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.1632G>A	p.Ala544Ala	synonymous	Exon 12 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152104 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00265 AC: 667 AN: 251390 AF XY: 0.00272

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00352 AC: 5147 AN: 1461886 Hom.: 16 Cov.: 32 AF XY: 0.00347 AC XY: 2526 AN XY: 727242

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 367 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86258

European-Finnish (FIN) AF: 0.00270 AC: 144 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00382 AC: 4251 AN: 1112004

Other (OTH) AF: 0.00308 AC: 186 AN: 60396

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152222 Hom.: 2 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74418

African (AFR) AF: 0.000602 AC: 25 AN: 41548

American (AMR) AF: 0.000327 AC: 5 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4794

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00322 AC: 219 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00318 Hom.: 0

Bravo AF: 0.00203

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Muscular dystrophy-dystroglycanopathy type B6 (2)
-	-	2	not specified (2)
-	-	1	LARGE1-related disorder (1)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.046
DANN	Benign	0.42
PhyloP100		-5.2
Mutation Taster		=98/2	polymorphism

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: rs74550830; hg19: chr22-33679277; COSMIC: COSV61659981;