14-50937871-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002863.5(PYGL):c.244-34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,552,696 control chromosomes in the GnomAD database, including 339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 31 hom., cov: 33)

Exomes 𝑓: 0.019 ( 308 hom. )

Consequence

PYGL
NM_002863.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.148

Publications

2 publications found

Variant links:

Genes affected

PYGL (HGNC:9725): (glycogen phosphorylase L) This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 15. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2011]

PYGL Gene-Disease associations (from GenCC):

glycogen storage disease VI
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

PYGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 14-50937871-C-T is Benign according to our data. Variant chr14-50937871-C-T is described in ClinVar as Benign. ClinVar VariationId is 258842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0221 (3358/152268) while in subpopulation AFR AF = 0.0366 (1519/41540). AF 95% confidence interval is 0.035. There are 31 homozygotes in GnomAd4. There are 1596 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002863.5. 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
	PYGL	NM_002863.5	MANE Select	c.244-34G>A		intron	N/A	NP_002854.3
	PYGL	NM_001163940.2		c.244-2686G>A		intron	N/A	NP_001157412.1	P06737-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PYGL	ENST00000216392.8	TSL:1 MANE Select	c.244-34G>A	intron	N/A	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5	TSL:1	c.244-34G>A	intron	N/A	ENSP00000431657.1	E9PK47
PYGL	ENST00000530336.2	TSL:1	n.311-34G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3354

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0365

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.0173

Gnomad SAS

AF:

0.0164

Gnomad FIN

AF:

0.00942

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0166

AC:

4123

AN:

248690

AF XY:

0.0164

show subpopulations

Gnomad AFR exome

AF:

0.0350

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.00757

Gnomad EAS exome

AF:

0.0132

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.0174

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0188

AC:

26380

AN:

1400428

Hom.:

308

Cov.:

AF XY:

0.0188

AC XY:

13172

AN XY:

700268

show subpopulations

African (AFR)

AF:

0.0366

AC:

1176

AN:

32156

American (AMR)

AF:

0.0116

AC:

518

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00752

AC:

194

AN:

25788

East Asian (EAS)

AF:

0.0247

AC:

975

AN:

39400

South Asian (SAS)

AF:

0.0174

AC:

1482

AN:

85046

European-Finnish (FIN)

AF:

0.0123

AC:

639

AN:

51748

Middle Eastern (MID)

AF:

0.0169

AC:

AN:

5518

European-Non Finnish (NFE)

AF:

0.0190

AC:

20055

AN:

1057752

Other (OTH)

AF:

0.0214

AC:

1248

AN:

58402

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1252

2505

3757

5010

6262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

776

1552

2328

3104

3880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0221

AC:

3358

AN:

152268

Hom.:

Cov.:

AF XY:

0.0214

AC XY:

1596

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0366

AC:

1519

AN:

41540

American (AMR)

AF:

0.0166

AC:

254

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3470

East Asian (EAS)

AF:

0.0173

AC:

AN:

5188

South Asian (SAS)

AF:

0.0164

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00942

AC:

100

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0182

AC:

1240

AN:

68020

Other (OTH)

AF:

0.0218

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

179

359

538

718

897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0205

Hom.:

Bravo

AF:

0.0226

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.85

(source)

DANN

Benign

0.29

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over