rs17722172

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_133642.5(LARGE1):c.2100C>T(p.Asn700Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0598 in 1,613,914 control chromosomes in the GnomAD database, including 3,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 220 hom., cov: 32)

Exomes 𝑓: 0.061 ( 3023 hom. )

Consequence

LARGE1
NM_133642.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.165

Publications

8 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 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=-0.61).

BP6

Variant 22-33274598-G-A is Benign according to our data. Variant chr22-33274598-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.165 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	NM_133642.5 link	c.2100C>T	p.Asn700Asn	synonymous_variant	Exon 15 of 15	ENST00000397394.8	NP_598397.1	O95461-1X5DR28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8 link	c.2100C>T	p.Asn700Asn	synonymous_variant	Exon 15 of 15	5	NM_133642.5	ENSP00000380549.2		O95461-1

Frequencies

GnomAD3 genomes

AF:

0.0463

AC:

7044

AN:

152122

Hom.:

220

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0127

Gnomad AMI

AF:

0.0706

Gnomad AMR

AF:

0.0557

Gnomad ASJ

AF:

0.0867

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.0350

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0694

Gnomad OTH

AF:

0.0564

GnomAD2 exomes

AF:

0.0472

AC:

11842

AN:

250860

AF XY:

0.0477

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.0335

Gnomad ASJ exome

AF:

0.0807

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0390

Gnomad NFE exome

AF:

0.0696

Gnomad OTH exome

AF:

0.0626

GnomAD4 exome

AF:

0.0612

AC:

89503

AN:

1461674

Hom.:

3023

Cov.:

AF XY:

0.0603

AC XY:

43876

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.0111

AC:

370

AN:

33480

American (AMR)

AF:

0.0352

AC:

1573

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0798

AC:

2086

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0198

AC:

1712

AN:

86252

European-Finnish (FIN)

AF:

0.0443

AC:

2367

AN:

53420

Middle Eastern (MID)

AF:

0.0723

AC:

417

AN:

5768

European-Non Finnish (NFE)

AF:

0.0695

AC:

77272

AN:

1111808

Other (OTH)

AF:

0.0613

AC:

3703

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

4797

9593

14390

19186

23983

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2784

5568

8352

11136

13920

<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:

0.0463

AC:

7042

AN:

152240

Hom.:

220

Cov.:

AF XY:

0.0436

AC XY:

3245

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0127

AC:

528

AN:

41564

American (AMR)

AF:

0.0555

AC:

848

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0867

AC:

301

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0143

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0350

AC:

371

AN:

10606

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0693

AC:

4714

AN:

68004

Other (OTH)

AF:

0.0563

AC:

119

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

329

659

988

1318

1647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0620

Hom.:

633

Bravo

AF:

0.0456

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0702

EpiControl

AF:

0.0711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Mar 05, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 30, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Muscular dystrophy-dystroglycanopathy type B6

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

2.8

(source)

DANN

Benign

0.89

PhyloP100

-0.17

Mutation Taster

=94/6

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over