rs116315896

chr11-64757794-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_005609.4(PYGM):c.645G>A(p.Lys215=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00838 in 1,614,182 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (69 hom.)
• Consequence: PYGM NM_005609.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6 O:1
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 11-64757794-C-T is Benign according to our data. Variant chr11-64757794-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95299.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=4, Likely_benign=2, not_provided=1}. Variant chr11-64757794-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00872 (12741/1461848) while in subpopulation NFE AF= 0.0106 (11758/1112008). AF 95% confidence interval is 0.0104. There are 69 homozygotes in gnomad4_exome. There are 6283 alleles in male gnomad4_exome subpopulation. Median coverage is 39. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4	c.645G>A	p.Lys215=	synonymous_variant	5/20	ENST00000164139.4
PYGM	NM_001164716.1	c.381G>A	p.Lys127=	synonymous_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4	c.645G>A	p.Lys215=	synonymous_variant	5/20	1	NM_005609.4	P1
PYGM	ENST00000377432.7	c.381G>A	p.Lys127=	synonymous_variant	3/18	2

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 792 AN: 152216 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00904

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00458 AC: 1151 AN: 251188 Hom.: 3 AF XY: 0.00461 AC XY: 626 AN XY: 135824

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00737

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00872 AC: 12741 AN: 1461848 Hom.: 69 Cov.: 39 AF XY: 0.00864 AC XY: 6283 AN XY: 727224

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00637

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.00111

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00793

GnomAD4 genome AF: 0.00519 AC: 791 AN: 152334 Hom.: 4 Cov.: 33 AF XY: 0.00470 AC XY: 350 AN XY: 74502

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00904

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00695 Hom.: 1

Bravo AF: 0.00578

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00856

EpiControl AF: 0.00806

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type V Uncertain:4 Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 05, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 24, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 14, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2023	Variant summary: PYGM c.645G>A alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computational tools predict no significant impact on normal splicing, with 3/4 computational tools predicting the variant abolishes a cryptic exonic 5' donor site. Experimental evidence suggests that this variant may affect mRNA splicing as transcripts from peripheral blood mononuclear cells showed the inclusion of intron 6 and an altered reading frame (Garcia-Consuegra_2016). In muscle tissue, the normal transcript can be identified, although with an expression of only 5% relative to controls, suggesting a "leaky" splice effect (Garcia-Consuegra_2009). However, in both studies splicing was examined in samples from compound heterozygous patients with Glycogen Storage Disease Type V and to our knowledge, the variant effect on splicing has yet to be investigated in isolation in a controlled experimental system. The variant allele was found at a frequency of 0.0084 in 1614182 control chromosomes, including 73 homozygotes, in the gnomAD database, predominantly at a frequency of 0.01 within the Non-Finnish European subpopulation. The observed variant frequency within Non-Finnish European control individuals is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Nevertheless, c.645G>A has been reported in the literature in compound heterozygous individuals affected with Glycogen Storage Disease, Type V (Garcia-Consuegra_2009, Lucia_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22250184, 34426522, 26913921, 19251976). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Four submitters have classified the variant as benign/likely benign, three classified it as VUS and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2012	- -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PYGM: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2022	BS1, BP4 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
Cadd	Benign	10
Dann	Benign	0.61

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

LitVar

Other links and lift over

dbSNP: rs116315896; hg19: chr11-64525266;