NM_005609.4:c.645G>A

Variant names:

• chr11-64757794-C-T
• rs116315896
• NM_005609.4:c.645G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_005609.4(PYGM):​c.645G>A​(p.Lys215Lys) 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:7 B:6 O:1
• Conservation: PhyloP100: 1.50
• Publications: 9 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: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 95299.
• BP7: Synonymous conserved (PhyloP=1.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00519 (791/152334) while in subpopulation NFE AF = 0.00904 (615/68034). AF 95% confidence interval is 0.00845. There are 4 homozygotes in GnomAd4. There are 350 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.645G>A	p.Lys215Lys	synonymous	Exon 5 of 20	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.381G>A	p.Lys127Lys	synonymous	Exon 3 of 18	NP_001158188.1	P11217-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	ENST00000164139.4	TSL:1 MANE Select	c.645G>A	p.Lys215Lys	synonymous	Exon 5 of 20	ENSP00000164139.3	P11217-1
	PYGM	ENST00000967737.1		c.645G>A	p.Lys215Lys	synonymous	Exon 5 of 21	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.645G>A	p.Lys215Lys	synonymous	Exon 5 of 20	ENSP00000608929.1

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

GnomAD2 exomes AF: 0.00458 AC: 1151 AN: 251188 AF XY: 0.00461

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 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

African (AFR) AF: 0.00102 AC: 34 AN: 33480

American (AMR) AF: 0.00637 AC: 285 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86258

European-Finnish (FIN) AF: 0.00111 AC: 59 AN: 53382

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0106 AC: 11758 AN: 1112008

Other (OTH) AF: 0.00793 AC: 479 AN: 60392

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

African (AFR) AF: 0.00142 AC: 59 AN: 41570

American (AMR) AF: 0.00562 AC: 86 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00904 AC: 615 AN: 68034

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00719 Hom.: 8

Bravo AF: 0.00578

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00856

EpiControl AF: 0.00806

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	1	Glycogen storage disease, type V (8)
-	-	3	not specified (3)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	10
DANN	Benign	0.61
PhyloP100		1.5
Mutation Taster		=97/3	disease causing (ClinVar)

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: rs116315896; hg19: chr11-64525266;