Genetic Variant LARGE2:p.Phe356Leu (chr11-45926501-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001300721.2(LARGE2):c.1068C>G(p.Phe356Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LARGE2
NM_001300721.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.71

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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	HGVSp	Effect	Exon Rank	Protein	UniProt
LARGE2	NM_001300721.2	MANE Select	c.1068C>G	p.Phe356Leu	missense	Exon 9 of 14	NP_001287650.1	Q8N3Y3
LARGE2	NM_152312.5		c.1068C>G	p.Phe356Leu	missense	Exon 9 of 14	NP_689525.3
LARGE2	NM_001300722.2		c.975C>G	p.Phe325Leu	missense	Exon 10 of 15	NP_001287651.1	E9PIZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LARGE2	ENST00000401752.6	TSL:1 MANE Select	c.1068C>G	p.Phe356Leu	missense	Exon 9 of 14	ENSP00000385235.1	Q8N3Y3
LARGE2	ENST00000325468.9	TSL:1	c.1068C>G	p.Phe356Leu	missense	Exon 8 of 13	ENSP00000324570.5	Q8N3Y3
LARGE2	ENST00000530437.5	TSL:1	n.139C>G		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251286

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.59

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.0

PhyloP100

4.7

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.3

REVEL

Benign

0.27

Sift

Benign

0.23

Sift4G

Benign

0.10

Polyphen

0.69

Vest4

0.86

MutPred

0.67

Gain of helix (P = 0.0117)

MVP

0.45

MPC

0.25

ClinPred

0.55

GERP RS

5.7

PromoterAI

0.055

Neutral

(source)

Varity_R

0.56

gMVP

0.83

Mutation Taster

=23/77

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over