11-64753682-G-C

Position:

chr11-64753682-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 14/22 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 (★★).

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

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 links:

PYGM (HGNC:):

PYGM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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/exons	MANE	Protein	UniProt
PYGM	NM_005609.4 linkuse as main transcript	c.1240C>G	p.Arg414Gly	missense_variant, splice_region_variant	11/20	ENST00000164139.4	NP_005600.1	P11217-1
PYGM	NM_001164716.1 linkuse as main transcript	c.976C>G	p.Arg326Gly	missense_variant, splice_region_variant	9/18		NP_001158188.1	P11217-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PYGM	ENST00000164139.4 linkuse as main transcript	c.1240C>G	p.Arg414Gly	missense_variant, splice_region_variant	11/20	1	NM_005609.4	ENSP00000164139.3	P11217-1
PYGM	ENST00000377432.7 linkuse as main transcript	c.976C>G	p.Arg326Gly	missense_variant, splice_region_variant	9/18	2		ENSP00000366650.3	P11217-2
PYGM	ENST00000460413.1 linkuse as main transcript	n.317C>G		splice_region_variant, non_coding_transcript_exon_variant	3/3	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

GnomAD3 exomes

AF:

0.0136

AC:

3137

AN:

230338

Hom.:

246

AF XY:

0.0100

AC XY:

1269

AN XY:

126638

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 SAS exome

AF:

0.000273

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

Gnomad4 AFR exome

AF:

0.186

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.00339

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000340

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000466

Gnomad4 OTH exome

AF:

0.0108

GnomAD4 genome

AF:

0.0534

AC:

8130

AN:

152170

Hom.:

736

Cov.:

AF XY:

0.0512

AC XY:

3806

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.185

Gnomad4 AMR

AF:

0.0193

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.0436

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 17, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over