Genetic Variant LARGE2:c.770-126G>C (chr11-45925913-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001300721.2(LARGE2):c.770-126G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 778,040 control chromosomes in the GnomAD database, including 19,834 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 3024 hom., cov: 33)

Exomes 𝑓: 0.23 ( 16810 hom. )

Consequence

LARGE2
NM_001300721.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.615

Publications

6 publications found

Variant links:

Genes affected

LARGE2 (HGNC:16522): (LARGE xylosyl- and glucuronyltransferase 2) Predicted to enable dystroglycan binding activity; glucuronosyltransferase activity; and xylosyltransferase activity. Involved in protein O-linked mannosylation. Predicted to be located in intracellular membrane-bounded organelle. Predicted to be active in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

LARGE2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300721.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LARGE2	NM_001300721.2	MANE Select	c.770-126G>C	intron	N/A	NP_001287650.1
LARGE2	NM_152312.5		c.770-126G>C	intron	N/A	NP_689525.3
LARGE2	NM_001300722.2		c.677-126G>C	intron	N/A	NP_001287651.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LARGE2	ENST00000401752.6	TSL:1 MANE Select	c.770-126G>C	intron	N/A	ENSP00000385235.1
LARGE2	ENST00000325468.9	TSL:1	c.770-126G>C	intron	N/A	ENSP00000324570.5
LARGE2	ENST00000531526.5	TSL:2	c.770-126G>C	intron	N/A	ENSP00000432869.1

Frequencies

GnomAD3 genomes

AF:

0.181

AC:

27547

AN:

152036

Hom.:

3024

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0671

Gnomad AMI

AF:

0.153

Gnomad AMR

AF:

0.167

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.195

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.265

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.168

GnomAD4 exome

AF:

0.225

AC:

141048

AN:

625886

Hom.:

16810

AF XY:

0.224

AC XY:

71678

AN XY:

320578

show subpopulations

African (AFR)

AF:

0.0614

AC:

956

AN:

15562

American (AMR)

AF:

0.177

AC:

3528

AN:

19878

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

2247

AN:

15046

East Asian (EAS)

AF:

0.167

AC:

5302

AN:

31762

South Asian (SAS)

AF:

0.187

AC:

9172

AN:

49146

European-Finnish (FIN)

AF:

0.256

AC:

9581

AN:

37442

Middle Eastern (MID)

AF:

0.165

AC:

416

AN:

2522

European-Non Finnish (NFE)

AF:

0.244

AC:

103045

AN:

422846

Other (OTH)

AF:

0.215

AC:

6801

AN:

31682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

5509

11018

16527

22036

27545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2002

4004

6006

8008

10010

<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:

0.181

AC:

27563

AN:

152154

Hom.:

3024

Cov.:

AF XY:

0.180

AC XY:

13375

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0674

AC:

2798

AN:

41528

American (AMR)

AF:

0.167

AC:

2547

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

481

AN:

3466

East Asian (EAS)

AF:

0.194

AC:

1005

AN:

5170

South Asian (SAS)

AF:

0.181

AC:

874

AN:

4816

European-Finnish (FIN)

AF:

0.265

AC:

2803

AN:

10592

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.243

AC:

16508

AN:

67990

Other (OTH)

AF:

0.169

AC:

356

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1133

2266

3398

4531

5664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.209

Hom.:

488

Bravo

AF:

0.167

Asia WGS

AF:

0.175

AC:

606

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.5

(source)

DANN

Benign

0.70

PhyloP100

0.61

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