rs11231865

Positions:

• chr11-64753097-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005609.4(PYGM):​c.1494C>T​(p.Pro498=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00609 in 1,613,600 control chromosomes in the GnomAD database, including 527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (282 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (245 hom.)
• Consequence: PYGM NM_005609.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -4.89

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=-0.8).
• BP6: Variant 11-64753097-G-A is Benign according to our data. Variant chr11-64753097-G-A is described in ClinVar as [Benign]. Clinvar id is 95292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGM	NM_005609.4	c.1494C>T	p.Pro498=	synonymous_variant	12/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.1230C>T	p.Pro410=	synonymous_variant	10/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.1494C>T	p.Pro498=	synonymous_variant	12/20	1	NM_005609.4	ENSP00000164139	P1
PYGM	ENST00000377432.7	c.1230C>T	p.Pro410=	synonymous_variant	10/18	2		ENSP00000366650

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5047 AN: 152144 Hom.: 280 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00862 AC: 2167 AN: 251466 Hom.: 113 AF XY: 0.00618 AC XY: 840 AN XY: 135910

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.00561

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00327 AC: 4774 AN: 1461338 Hom.: 245 Cov.: 32 AF XY: 0.00275 AC XY: 2002 AN XY: 727002

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.00640

Gnomad4 ASJ exome AF: 0.00333

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.0332 AC: 5053 AN: 152262 Hom.: 282 Cov.: 33 AF XY: 0.0313 AC XY: 2327 AN XY: 74450

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.00934 Hom.: 79

Bravo AF: 0.0371

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type V Benign:3 Other: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	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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	May 24, 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)	May 06, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.0
DANN	Benign	0.74

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: rs11231865; hg19: chr11-64520569; COSMIC: COSV51217162; COSMIC: COSV51217162;