22-33650564-C-T

Variant names:

• chr22-33650564-C-T
• rs116164106
• NM_133642.5:c.211G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_133642.5(LARGE1):​c.211G>A​(p.Glu71Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,607,980 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: LARGE1 NM_133642.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 5.24
• 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

  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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030572116).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000873 (133/152368) while in subpopulation NFE AF = 0.0016 (109/68040). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.211G>A	p.Glu71Lys	missense	Exon 3 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.211G>A	p.Glu71Lys	missense	Exon 4 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.211G>A	p.Glu71Lys	missense	Exon 3 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.211G>A	p.Glu71Lys	missense	Exon 3 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.211G>A	p.Glu71Lys	missense	Exon 4 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.211G>A	p.Glu71Lys	missense	Exon 3 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000728 AC: 178 AN: 244590 AF XY: 0.000684

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad FIN exome AF: 0.000285

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.00140 AC: 2044 AN: 1455612 Hom.: 2 Cov.: 32 AF XY: 0.00139 AC XY: 1008 AN XY: 724516

African (AFR) AF: 0.000299 AC: 10 AN: 33474

American (AMR) AF: 0.000582 AC: 26 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.000529 AC: 21 AN: 39696

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86230

European-Finnish (FIN) AF: 0.000274 AC: 13 AN: 47436

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5740

European-Non Finnish (NFE) AF: 0.00168 AC: 1866 AN: 1111876

Other (OTH) AF: 0.00161 AC: 97 AN: 60350

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74508

African (AFR) AF: 0.000168 AC: 7 AN: 41584

American (AMR) AF: 0.000718 AC: 11 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00160 AC: 109 AN: 68040

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000920 Hom.: 0

Bravo AF: 0.000865

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000701 AC: 85

EpiCase AF: 0.00164

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	2	-	Muscular dystrophy-dystroglycanopathy type B6 (2)
-	1	-	Muscular dystrophy (1)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)
-	1	-	Muscular dystrophy-dystroglycanopathy type B6;C3150414:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.078
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.14
Sift	Benign	0.19	T
Sift4G	Benign	0.39	T
Polyphen		0.0040	B
Vest4		0.53
MVP		0.35
MPC		0.59
ClinPred		0.017	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.58
Mutation Taster		=85/15	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: rs116164106; hg19: chr22-34046550; COSMIC: COSV61660426; COSMIC: COSV61660426;