rs139726186

Positions:

• chr11-64754768-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_005609.4(PYGM):​c.924C>T​(p.Ile308Ile) variant causes a synonymous change. The variant allele was found at a frequency of 0.0022 in 1,613,948 control chromosomes in the GnomAD database, including 10 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 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (10 hom.)
• Consequence: PYGM NM_005609.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 4.83

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 11-64754768-G-A is Benign according to our data. Variant chr11-64754768-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198831.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGM	NM_005609.4	c.924C>T	p.Ile308Ile	synonymous_variant	8/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.660C>T	p.Ile220Ile	synonymous_variant	6/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.924C>T	p.Ile308Ile	synonymous_variant	8/20	1	NM_005609.4	ENSP00000164139.3
PYGM	ENST00000377432.7	c.660C>T	p.Ile220Ile	synonymous_variant	6/18	2		ENSP00000366650.3

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 261 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00144 AC: 361 AN: 250178 Hom.: 1 AF XY: 0.00132 AC XY: 179 AN XY: 135596

Gnomad AFR exome AF: 0.000683

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00225 AC: 3287 AN: 1461622 Hom.: 10 Cov.: 33 AF XY: 0.00212 AC XY: 1542 AN XY: 727126

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74484

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00265

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00211 Hom.: 0

Bravo AF: 0.00195

EpiCase AF: 0.00267

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type V Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 25, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PYGM: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.94

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: rs139726186; hg19: chr11-64522240;