11-64753682-G-C

Variant names:

• chr11-64753682-G-C
• rs11231866
• NM_005609.4:c.1240C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_005609.4(PYGM):​c.1240C>G​(p.Arg414Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,605,310 control chromosomes in the GnomAD database, including 1,362 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R414Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (736 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (626 hom.)
• Consequence: PYGM NM_005609.4 missense, splice_region
• Scores: Splicing: ADA: 0.001135
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.0260
• 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: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.046884 (below the threshold of 3.09). Trascript score misZ: 1.6804 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease V.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004038334).
• BP6: Variant 11-64753682-G-C is Benign according to our data. Variant chr11-64753682-G-C is described in ClinVar as Benign. ClinVar VariationId is 95289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 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.1240C>G	p.Arg414Gly	missense splice_region	Exon 11 of 20	NP_005600.1
	PYGM	NM_001164716.1		c.976C>G	p.Arg326Gly	missense splice_region	Exon 9 of 18	NP_001158188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	ENST00000164139.4	TSL:1 MANE Select	c.1240C>G	p.Arg414Gly	missense splice_region	Exon 11 of 20	ENSP00000164139.3
	PYGM	ENST00000967737.1		c.1339C>G	p.Arg447Gly	missense splice_region	Exon 12 of 21	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.1156C>G	p.Arg386Gly	missense splice_region	Exon 11 of 20	ENSP00000608929.1

Frequencies

GnomAD3 genomes AF: 0.0534 AC: 8120 AN: 152052 Hom.: 736 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.0441

GnomAD2 exomes AF: 0.0136 AC: 3137 AN: 230338 AF XY: 0.0100

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.00928

Gnomad ASJ exome AF: 0.00355

Gnomad EAS exome AF: 0.0000567

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000755

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.00550 AC: 7987 AN: 1453140 Hom.: 626 Cov.: 45 AF XY: 0.00469 AC XY: 3391 AN XY: 722592

African (AFR) AF: 0.186 AC: 6212 AN: 33382

American (AMR) AF: 0.0103 AC: 455 AN: 44284

Ashkenazi Jewish (ASJ) AF: 0.00339 AC: 88 AN: 25996

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39482

South Asian (SAS) AF: 0.000340 AC: 29 AN: 85278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49622

Middle Eastern (MID) AF: 0.00728 AC: 34 AN: 4668

European-Non Finnish (NFE) AF: 0.000466 AC: 518 AN: 1110408

Other (OTH) AF: 0.0108 AC: 650 AN: 60020

GnomAD4 genome AF: 0.0534 AC: 8130 AN: 152170 Hom.: 736 Cov.: 33 AF XY: 0.0512 AC XY: 3806 AN XY: 74394

African (AFR) AF: 0.185 AC: 7674 AN: 41468

American (AMR) AF: 0.0193 AC: 295 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 67990

Other (OTH) AF: 0.0436 AC: 92 AN: 2108

Alfa AF: 0.00403 Hom.: 7

Bravo AF: 0.0599

ESP6500AA AF: 0.180 AC: 788

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.0165 AC: 1989

Asia WGS AF: 0.00808 AC: 30 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.026
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.33
Sift	Benign	0.18	T
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.77
MPC		0.38
ClinPred		0.015	T
GERP RS		1.8
Varity_R		0.52
gMVP		0.77
Mutation Taster		=62/38	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.20
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: rs11231866; hg19: chr11-64521154; COSMIC: COSV51217197; COSMIC: COSV51217197;