chr11-64752454-G-C

Position:

• chr11-64752454-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005609.4(PYGM):​c.1569C>G​(p.Leu523Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,614,210 control chromosomes in the GnomAD database, including 237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 32)
  • Exomes 𝑓: 0.016 (225 hom.)
• Consequence: PYGM NM_005609.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.277

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 11-64752454-G-C is Benign according to our data. Variant chr11-64752454-G-C is described in ClinVar as [Benign]. Clinvar id is 95293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64752454-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.277 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0117 (1784/152366) while in subpopulation NFE AF= 0.0177 (1202/68034). AF 95% confidence interval is 0.0168. There are 12 homozygotes in gnomad4. There are 812 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGM	NM_005609.4	c.1569C>G	p.Leu523Leu	synonymous_variant	13/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.1305C>G	p.Leu435Leu	synonymous_variant	11/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.1569C>G	p.Leu523Leu	synonymous_variant	13/20	1	NM_005609.4	ENSP00000164139.3
PYGM	ENST00000377432.7	c.1305C>G	p.Leu435Leu	synonymous_variant	11/18	2		ENSP00000366650.3

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1784 AN: 152248 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00477

Gnomad AMI AF: 0.0571

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00602

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0100 AC: 2518 AN: 251342 Hom.: 23 AF XY: 0.0101 AC XY: 1368 AN XY: 135884

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.00801

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00591

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0163 AC: 23833 AN: 1461844 Hom.: 225 Cov.: 32 AF XY: 0.0158 AC XY: 11488 AN XY: 727228

Gnomad4 AFR exome AF: 0.00597

Gnomad4 AMR exome AF: 0.00841

Gnomad4 ASJ exome AF: 0.00364

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00711

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0117 AC: 1784 AN: 152366 Hom.: 12 Cov.: 32 AF XY: 0.0109 AC XY: 812 AN XY: 74498

Gnomad4 AFR AF: 0.00476

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00602

Gnomad4 NFE AF: 0.0177

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0141 Hom.: 4

Bravo AF: 0.0126

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0164

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type V Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2012	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 17, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.4
DANN	Benign	0.61

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

LitVar

Other links and lift over

dbSNP: rs114138772; hg19: chr11-64519926;