chr22-33283252-T-C

Variant names:

• chr22-33283252-T-C
• rs11913417
• NM_133642.5:c.1827A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_133642.5(LARGE1):​c.1827A>G​(p.Ser609Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00976 in 1,614,120 control chromosomes in the GnomAD database, including 386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (90 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (296 hom.)
• Consequence: LARGE1 NM_133642.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.84
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-33283252-T-C is Benign according to our data. Variant chr22-33283252-T-C is described in ClinVar as Benign. ClinVar VariationId is 95169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0562 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.1827A>G	p.Ser609Ser	synonymous	Exon 13 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.1827A>G	p.Ser609Ser	synonymous	Exon 14 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.1827A>G	p.Ser609Ser	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.1827A>G	p.Ser609Ser	synonymous	Exon 13 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.1827A>G	p.Ser609Ser	synonymous	Exon 14 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.1671A>G	p.Ser557Ser	synonymous	Exon 12 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3393 AN: 152116 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0545

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.0159 AC: 3992 AN: 251418 AF XY: 0.0173

Gnomad AFR exome AF: 0.0603

Gnomad AMR exome AF: 0.00789

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.00283

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00845 AC: 12357 AN: 1461886 Hom.: 296 Cov.: 32 AF XY: 0.00999 AC XY: 7263 AN XY: 727242

African (AFR) AF: 0.0637 AC: 2131 AN: 33476

American (AMR) AF: 0.00923 AC: 413 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 752 AN: 26136

East Asian (EAS) AF: 0.00159 AC: 63 AN: 39700

South Asian (SAS) AF: 0.0578 AC: 4982 AN: 86258

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53420

Middle Eastern (MID) AF: 0.0383 AC: 221 AN: 5768

European-Non Finnish (NFE) AF: 0.00257 AC: 2861 AN: 1112008

Other (OTH) AF: 0.0149 AC: 902 AN: 60396

GnomAD4 genome AF: 0.0223 AC: 3399 AN: 152234 Hom.: 90 Cov.: 32 AF XY: 0.0231 AC XY: 1719 AN XY: 74432

African (AFR) AF: 0.0581 AC: 2416 AN: 41548

American (AMR) AF: 0.0160 AC: 245 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3470

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5164

South Asian (SAS) AF: 0.0545 AC: 263 AN: 4822

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00372 AC: 253 AN: 68014

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.0131 Hom.: 28

Bravo AF: 0.0252

Asia WGS AF: 0.0310 AC: 106 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00634

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Muscular dystrophy-dystroglycanopathy type B6 (2)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.15
DANN	Benign	0.36
PhyloP100		-1.8
Mutation Taster		=98/2	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: rs11913417; hg19: chr22-33679238;