rs139726186

Variant names:

• chr11-64754768-G-A
• rs139726186
• NM_005609.4:c.924C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64754768-G-A
• chr11-64754768-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_005609.4(PYGM):​c.924C>T​(p.Ile308Ile) variant causes a synonymous change. The variant allele was found at a frequency of 0.0022 in 1,613,948 control chromosomes in the GnomAD database, including 10 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 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (10 hom.)
• Consequence: PYGM NM_005609.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 4.83
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 11-64754768-G-A is Benign according to our data. Variant chr11-64754768-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198831.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.924C>T	p.Ile308Ile	synonymous	Exon 8 of 20	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.660C>T	p.Ile220Ile	synonymous	Exon 6 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.924C>T	p.Ile308Ile	synonymous	Exon 8 of 20	ENSP00000164139.3	P11217-1
	PYGM	ENST00000967737.1		c.1023C>T	p.Ile341Ile	synonymous	Exon 9 of 21	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.840C>T	p.Ile280Ile	synonymous	Exon 8 of 20	ENSP00000608929.1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 261 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00144 AC: 361 AN: 250178 AF XY: 0.00132

Gnomad AFR exome AF: 0.000683

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00225 AC: 3287 AN: 1461622 Hom.: 10 Cov.: 33 AF XY: 0.00212 AC XY: 1542 AN XY: 727126

African (AFR) AF: 0.000269 AC: 9 AN: 33474

American (AMR) AF: 0.00237 AC: 106 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26134

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

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86252

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53270

Middle Eastern (MID) AF: 0.00227 AC: 13 AN: 5724

European-Non Finnish (NFE) AF: 0.00262 AC: 2910 AN: 1111974

Other (OTH) AF: 0.00298 AC: 180 AN: 60386

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74484

African (AFR) AF: 0.000481 AC: 20 AN: 41570

American (AMR) AF: 0.00248 AC: 38 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00265 AC: 180 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00216 Hom.: 0

Bravo AF: 0.00195

EpiCase AF: 0.00267

EpiControl AF: 0.00237

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	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		4.8
Mutation Taster		=97/3	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: rs139726186; hg19: chr11-64522240;