Genetic Variant NM_133642.5:c.576C>T (chr22-33604474-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_133642.5(LARGE1):c.576C>T(p.Pro192Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,614,018 control chromosomes in the GnomAD database, including 845 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. P192P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.023 ( 67 hom., cov: 32)

Exomes 𝑓: 0.030 ( 778 hom. )

Consequence

LARGE1
NM_133642.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.37

Publications

5 publications found

Variant links:

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

LARGE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 22-33604474-G-A is Benign according to our data. Variant chr22-33604474-G-A is described in ClinVar as Benign. ClinVar VariationId is 95176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.37 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0232 (3531/152234) while in subpopulation NFE AF = 0.0326 (2216/68014). AF 95% confidence interval is 0.0315. There are 67 homozygotes in GnomAd4. There are 1704 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 67 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LARGE1	NM_133642.5	MANE Select	c.576C>T	p.Pro192Pro	synonymous	Exon 5 of 15	NP_598397.1
LARGE1	NM_001362949.2		c.576C>T	p.Pro192Pro	synonymous	Exon 6 of 16	NP_001349878.1
LARGE1	NM_001362951.2		c.576C>T	p.Pro192Pro	synonymous	Exon 5 of 15	NP_001349880.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.576C>T	p.Pro192Pro	synonymous	Exon 5 of 15	ENSP00000380549.2
LARGE1	ENST00000354992.7	TSL:1	c.576C>T	p.Pro192Pro	synonymous	Exon 6 of 16	ENSP00000347088.2
LARGE1	ENST00000402320.6	TSL:1	c.576C>T	p.Pro192Pro	synonymous	Exon 5 of 14	ENSP00000385223.1

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3532

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0241

Gnomad ASJ

AF:

0.0530

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.0349

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0326

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0235

AC:

5905

AN:

251256

AF XY:

0.0240

show subpopulations

Gnomad AFR exome

AF:

0.00517

Gnomad AMR exome

AF:

0.0158

Gnomad ASJ exome

AF:

0.0499

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0318

Gnomad NFE exome

AF:

0.0304

Gnomad OTH exome

AF:

0.0277

GnomAD4 exome

AF:

0.0302

AC:

44099

AN:

1461784

Hom.:

778

Cov.:

AF XY:

0.0299

AC XY:

21733

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00439

AC:

147

AN:

33476

American (AMR)

AF:

0.0172

AC:

769

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0491

AC:

1283

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39694

South Asian (SAS)

AF:

0.0162

AC:

1401

AN:

86258

European-Finnish (FIN)

AF:

0.0328

AC:

1751

AN:

53398

Middle Eastern (MID)

AF:

0.0362

AC:

209

AN:

5766

European-Non Finnish (NFE)

AF:

0.0332

AC:

36870

AN:

1111948

Other (OTH)

AF:

0.0276

AC:

1665

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2411

4821

7232

9642

12053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1386

2772

4158

5544

6930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0232

AC:

3531

AN:

152234

Hom.:

Cov.:

AF XY:

0.0229

AC XY:

1704

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00578

AC:

240

AN:

41548

American (AMR)

AF:

0.0241

AC:

368

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0530

AC:

184

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.0172

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0349

AC:

370

AN:

10602

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0326

AC:

2216

AN:

68014

Other (OTH)

AF:

0.0284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

181

362

544

725

906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0275

Hom.:

Bravo

AF:

0.0217

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0334

EpiControl

AF:

0.0297

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Muscular dystrophy-dystroglycanopathy type B6 (2)

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

3.1

(source)

DANN

Benign

0.67

PhyloP100

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over