11-64753470-G-T

Variant names:

• chr11-64753470-G-T
• rs2959652
• NM_005609.4:c.1403+49C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005609.4(PYGM):​c.1403+49C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 1,533,780 control chromosomes in the GnomAD database, including 574,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (44155 hom., cov: 30)
  • Exomes 𝑓: 0.87 (530055 hom.)
• Consequence: PYGM NM_005609.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.737
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease V

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-64753470-G-T is Benign according to our data. Variant chr11-64753470-G-T is described in ClinVar as Benign. ClinVar VariationId is 259830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005609.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	NM_005609.4	MANE Select	c.1403+49C>A		intron	N/A	NP_005600.1
	PYGM	NM_001164716.1		c.1139+49C>A		intron	N/A	NP_001158188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	ENST00000164139.4	TSL:1 MANE Select	c.1403+49C>A		intron	N/A	ENSP00000164139.3
	PYGM	ENST00000967737.1		c.1502+49C>A		intron	N/A	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.1319+49C>A		intron	N/A	ENSP00000608929.1

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111529 AN: 151642 Hom.: 44161 Cov.: 30

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.967

Gnomad AMR AF: 0.703

Gnomad ASJ AF: 0.850

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.889

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.899

Gnomad OTH AF: 0.764

GnomAD2 exomes AF: 0.791 AC: 116721 AN: 147636 AF XY: 0.804

Gnomad AFR exome AF: 0.423

Gnomad AMR exome AF: 0.679

Gnomad ASJ exome AF: 0.855

Gnomad EAS exome AF: 0.618

Gnomad FIN exome AF: 0.887

Gnomad NFE exome AF: 0.903

Gnomad OTH exome AF: 0.842

GnomAD4 exome AF: 0.870 AC: 1202719 AN: 1382020 Hom.: 530055 Cov.: 39 AF XY: 0.870 AC XY: 592518 AN XY: 681078

African (AFR) AF: 0.423 AC: 13498 AN: 31892

American (AMR) AF: 0.675 AC: 24726 AN: 36652

Ashkenazi Jewish (ASJ) AF: 0.853 AC: 20625 AN: 24172

East Asian (EAS) AF: 0.598 AC: 21838 AN: 36534

South Asian (SAS) AF: 0.802 AC: 62944 AN: 78512

European-Finnish (FIN) AF: 0.891 AC: 31204 AN: 35002

Middle Eastern (MID) AF: 0.867 AC: 4845 AN: 5588

European-Non Finnish (NFE) AF: 0.906 AC: 974624 AN: 1076064

Other (OTH) AF: 0.840 AC: 48415 AN: 57604

GnomAD4 genome AF: 0.735 AC: 111555 AN: 151760 Hom.: 44155 Cov.: 30 AF XY: 0.734 AC XY: 54401 AN XY: 74140

African (AFR) AF: 0.431 AC: 17845 AN: 41398

American (AMR) AF: 0.703 AC: 10713 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.850 AC: 2944 AN: 3462

East Asian (EAS) AF: 0.617 AC: 3178 AN: 5152

South Asian (SAS) AF: 0.792 AC: 3801 AN: 4798

European-Finnish (FIN) AF: 0.889 AC: 9378 AN: 10554

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.898 AC: 60959 AN: 67846

Other (OTH) AF: 0.762 AC: 1601 AN: 2102

Alfa AF: 0.819 Hom.: 10765

Bravo AF: 0.707

Asia WGS AF: 0.688 AC: 2391 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glycogen storage disease, type V (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.85
PhyloP100		0.74
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2959652; hg19: chr11-64520942; COSMIC: COSV51217669; COSMIC: COSV51217669;