11-64753682-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_005609.4(PYGM):c.1240C>G(p.Arg414Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,605,310 control chromosomes in the GnomAD database, including 1,362 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R414W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.053 ( 736 hom., cov: 33)

Exomes 𝑓: 0.0055 ( 626 hom. )

Consequence

PYGM
NM_005609.4 missense, splice_region

Scores

Splicing: ADA: 0.001135

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.0260

Publications

11 publications found

Variant links:

Genes affected

PYGM (HGNC:9726): (glycogen phosphorylase, muscle associated) This gene encodes a muscle enzyme involved in glycogenolysis. Highly similar enzymes encoded by different genes are found in liver and brain. Mutations in this gene are associated with McArdle disease (myophosphorylase deficiency), a glycogen storage disease of muscle. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]

PYGM Gene-Disease associations (from GenCC):

glycogen storage disease V
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

PYGM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.046884 (below the threshold of 3.09). Trascript score misZ: 1.6804 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease V.

BP4

Computational evidence support a benign effect (MetaRNN=0.004038334).

BP6

Variant 11-64753682-G-C is Benign according to our data. Variant chr11-64753682-G-C is described in ClinVar as [Benign]. Clinvar id is 95289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4 link	c.1240C>G	p.Arg414Gly	missense_variant, splice_region_variant	Exon 11 of 20	ENST00000164139.4	NP_005600.1	P11217-1
PYGM	NM_001164716.1 link	c.976C>G	p.Arg326Gly	missense_variant, splice_region_variant	Exon 9 of 18		NP_001158188.1	P11217-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGM	ENST00000164139.4 link	c.1240C>G	p.Arg414Gly	missense_variant, splice_region_variant	Exon 11 of 20	1	NM_005609.4	ENSP00000164139.3	P11217-1
PYGM	ENST00000377432.7 link	c.976C>G	p.Arg326Gly	missense_variant, splice_region_variant	Exon 9 of 18	2		ENSP00000366650.3	P11217-2
PYGM	ENST00000460413.1 link	n.317C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0534

AC:

8120

AN:

152052

Hom.:

736

Cov.:

show subpopulations

Gnomad AFR

AF:

0.185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0193

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.0441

GnomAD2 exomes

AF:

0.0136

AC:

3137

AN:

230338

AF XY:

0.0100

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.00928

Gnomad ASJ exome

AF:

0.00355

Gnomad EAS exome

AF:

0.0000567

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000755

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.00550

AC:

7987

AN:

1453140

Hom.:

626

Cov.:

AF XY:

0.00469

AC XY:

3391

AN XY:

722592

show subpopulations

African (AFR)

AF:

0.186

AC:

6212

AN:

33382

American (AMR)

AF:

0.0103

AC:

455

AN:

44284

Ashkenazi Jewish (ASJ)

AF:

0.00339

AC:

AN:

25996

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39482

South Asian (SAS)

AF:

0.000340

AC:

AN:

85278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49622

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

4668

European-Non Finnish (NFE)

AF:

0.000466

AC:

518

AN:

1110408

Other (OTH)

AF:

0.0108

AC:

650

AN:

60020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

420

840

1260

1680

2100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0534

AC:

8130

AN:

152170

Hom.:

736

Cov.:

AF XY:

0.0512

AC XY:

3806

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.185

AC:

7674

AN:

41468

American (AMR)

AF:

0.0193

AC:

295

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

67990

Other (OTH)

AF:

0.0436

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

334

667

1001

1334

1668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00403

Hom.:

Bravo

AF:

0.0599

ESP6500AA

AF:

0.180

AC:

788

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.0165

AC:

1989

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type V

Benign:3Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Nov 13, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.42

.;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.97

.;L

PhyloP100

0.026

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.18

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.0

.;B

Vest4

0.77

MPC

0.38

ClinPred

0.015

GERP RS

1.8

Varity_R

0.52

gMVP

0.77

Mutation Taster

=62/38

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0011

dbscSNV1_RF

Benign

0.20

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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11-64753682-G-C

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