rs368602234

Variant names:

• chr11-64754246-A-AG
• rs368602234
• NM_005609.4:c.1092+6dupC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005609.4(PYGM):​c.1092+6dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,610,438 control chromosomes in the GnomAD database, including 23 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0065 (12 hom., cov: 31)
  • Exomes 𝑓: 0.00066 (11 hom.)
• Consequence: PYGM NM_005609.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 1.49
• Publications: 1 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 -9 ACMG points.

• BP6: Variant 11-64754246-A-AG is Benign according to our data. Variant chr11-64754246-A-AG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259829.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00646 (982/152118) while in subpopulation AFR AF = 0.0229 (951/41516). AF 95% confidence interval is 0.0217. There are 12 homozygotes in GnomAd4. There are 454 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.1092+6dupC		splice_region intron	N/A	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.828+6dupC		splice_region intron	N/A	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.1092+6_1092+7insC		splice_region intron	N/A	ENSP00000164139.3	P11217-1
	PYGM	ENST00000967737.1		c.1191+6_1191+7insC		splice_region intron	N/A	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.1008+6_1008+7insC		splice_region intron	N/A	ENSP00000608929.1

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 972 AN: 152000 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00163 AC: 409 AN: 251006 AF XY: 0.00118

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000664 AC: 969 AN: 1458320 Hom.: 11 Cov.: 33 AF XY: 0.000579 AC XY: 420 AN XY: 725682

African (AFR) AF: 0.0238 AC: 795 AN: 33404

American (AMR) AF: 0.00110 AC: 49 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53108

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1109054

Other (OTH) AF: 0.00168 AC: 101 AN: 60276

GnomAD4 genome AF: 0.00646 AC: 982 AN: 152118 Hom.: 12 Cov.: 31 AF XY: 0.00611 AC XY: 454 AN XY: 74360

African (AFR) AF: 0.0229 AC: 951 AN: 41516

American (AMR) AF: 0.00170 AC: 26 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67924

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00298 Hom.: 1

Bravo AF: 0.00739

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Glycogen storage disease, type V (4)
-	1	1	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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: rs368602234; hg19: chr11-64521718;