rs589691

Variant names:

• chr11-64757744-C-T
• rs589691
• NM_005609.4:c.660+35G>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.660+35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.849 in 1,613,552 control chromosomes in the GnomAD database, including 597,641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (42040 hom., cov: 32)
  • Exomes 𝑓: 0.86 (555601 hom.)
• Consequence: PYGM NM_005609.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.270
• Publications: 28 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: Genomics England PanelApp, ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-64757744-C-T is Benign according to our data. Variant chr11-64757744-C-T is described in ClinVar as Benign. ClinVar VariationId is 259840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.892 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.660+35G>A		intron	N/A	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.396+35G>A		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.660+35G>A		intron	N/A	ENSP00000164139.3	P11217-1
	PYGM	ENST00000967737.1		c.660+35G>A		intron	N/A	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.660+35G>A		intron	N/A	ENSP00000608929.1

Frequencies

GnomAD3 genomes AF: 0.697 AC: 106032 AN: 152028 Hom.: 42049 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.967

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.889

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.898

Gnomad OTH AF: 0.730

GnomAD2 exomes AF: 0.793 AC: 198705 AN: 250478 AF XY: 0.810

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.851

Gnomad EAS exome AF: 0.616

Gnomad FIN exome AF: 0.885

Gnomad NFE exome AF: 0.902

Gnomad OTH exome AF: 0.840

GnomAD4 exome AF: 0.864 AC: 1263079 AN: 1461406 Hom.: 555601 Cov.: 53 AF XY: 0.865 AC XY: 628821 AN XY: 726994

African (AFR) AF: 0.288 AC: 9631 AN: 33468

American (AMR) AF: 0.664 AC: 29654 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 22167 AN: 26130

East Asian (EAS) AF: 0.597 AC: 23703 AN: 39686

South Asian (SAS) AF: 0.804 AC: 69324 AN: 86244

European-Finnish (FIN) AF: 0.888 AC: 47317 AN: 53290

Middle Eastern (MID) AF: 0.854 AC: 4921 AN: 5762

European-Non Finnish (NFE) AF: 0.905 AC: 1006163 AN: 1111764

Other (OTH) AF: 0.831 AC: 50199 AN: 60380

GnomAD4 genome AF: 0.697 AC: 106048 AN: 152146 Hom.: 42040 Cov.: 32 AF XY: 0.697 AC XY: 51815 AN XY: 74376

African (AFR) AF: 0.302 AC: 12526 AN: 41480

American (AMR) AF: 0.683 AC: 10444 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 2939 AN: 3472

East Asian (EAS) AF: 0.617 AC: 3178 AN: 5148

South Asian (SAS) AF: 0.792 AC: 3829 AN: 4834

European-Finnish (FIN) AF: 0.889 AC: 9430 AN: 10608

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.898 AC: 61040 AN: 68004

Other (OTH) AF: 0.728 AC: 1534 AN: 2106

Alfa AF: 0.834 Hom.: 162259

Bravo AF: 0.665

Asia WGS AF: 0.680 AC: 2365 AN: 3478

ClinVar

ClinVar submissions

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	-0.83
CADD	Benign	1.0
DANN	Benign	0.30
PhyloP100		-0.27
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs589691;

hg19: chr11-64525216;

COSMIC: COSV51217675;

COSMIC: COSV51217675;