22-33650610-C-G

Variant names:

• chr22-33650610-C-G
• rs63446460
• NM_133642.5:c.165G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_133642.5(LARGE1):​c.165G>C​(p.Thr55Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,604,364 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T55T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (51 hom.)
• Consequence: LARGE1 NM_133642.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.52
• 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 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=-0.77).
• BP6: Variant 22-33650610-C-G is Benign according to our data. Variant chr22-33650610-C-G is described in ClinVar as Benign. ClinVar VariationId is 158805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (2064/152302) while in subpopulation AFR AF = 0.0464 (1931/41572). AF 95% confidence interval is 0.0447. There are 41 homozygotes in GnomAd4. There are 1015 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 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.165G>C	p.Thr55Thr	synonymous	Exon 3 of 15	NP_598397.1
	LARGE1	NM_001362949.2		c.165G>C	p.Thr55Thr	synonymous	Exon 4 of 16	NP_001349878.1
	LARGE1	NM_001362951.2		c.165G>C	p.Thr55Thr	synonymous	Exon 3 of 15	NP_001349880.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.165G>C	p.Thr55Thr	synonymous	Exon 3 of 15	ENSP00000380549.2
	LARGE1	ENST00000354992.7	TSL:1	c.165G>C	p.Thr55Thr	synonymous	Exon 4 of 16	ENSP00000347088.2
	LARGE1	ENST00000402320.6	TSL:1	c.165G>C	p.Thr55Thr	synonymous	Exon 3 of 14	ENSP00000385223.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2033 AN: 152184 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00362 AC: 869 AN: 240094 AF XY: 0.00267

Gnomad AFR exome AF: 0.0478

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad FIN exome AF: 0.000129

Gnomad NFE exome AF: 0.000164

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00146 AC: 2120 AN: 1452062 Hom.: 51 Cov.: 32 AF XY: 0.00126 AC XY: 913 AN XY: 722832

African (AFR) AF: 0.0472 AC: 1578 AN: 33464

American (AMR) AF: 0.00326 AC: 146 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86238

European-Finnish (FIN) AF: 0.0000679 AC: 3 AN: 44208

Middle Eastern (MID) AF: 0.00407 AC: 22 AN: 5402

European-Non Finnish (NFE) AF: 0.0000899 AC: 100 AN: 1111910

Other (OTH) AF: 0.00410 AC: 247 AN: 60288

GnomAD4 genome AF: 0.0136 AC: 2064 AN: 152302 Hom.: 41 Cov.: 32 AF XY: 0.0136 AC XY: 1015 AN XY: 74470

African (AFR) AF: 0.0464 AC: 1931 AN: 41572

American (AMR) AF: 0.00693 AC: 106 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68022

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00352 Hom.: 3

Bravo AF: 0.0163

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	-0.77
CADD	Benign	0.22
DANN	Benign	0.75
PhyloP100		-4.5
Mutation Taster		=100/0	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: rs63446460; hg19: chr22-34046596;