chr20-25248324-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002862.4(PYGB):​c.146C>T​(p.Pro49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PYGB
NM_002862.4 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.41
Variant links:
Genes affected
PYGB (HGNC:9723): (glycogen phosphorylase B) The protein encoded by this gene is a glycogen phosphorylase found predominantly in the brain. The encoded protein forms homodimers which can associate into homotetramers, the enzymatically active form of glycogen phosphorylase. The activity of this enzyme is positively regulated by AMP and negatively regulated by ATP, ADP, and glucose-6-phosphate. This enzyme catalyzes the rate-determining step in glycogen degradation. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PYGBNM_002862.4 linkc.146C>T p.Pro49Leu missense_variant Exon 1 of 20 ENST00000216962.9 NP_002853.2 P11216
PYGBXM_047440342.1 linkc.146C>T p.Pro49Leu missense_variant Exon 1 of 16 XP_047296298.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PYGBENST00000216962.9 linkc.146C>T p.Pro49Leu missense_variant Exon 1 of 20 1 NM_002862.4 ENSP00000216962.3 P11216

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000417
AC:
1
AN:
239974
Hom.:
0
AF XY:
0.00000767
AC XY:
1
AN XY:
130388
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000911
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1452076
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
722262
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000118
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
ExAC
AF:
0.00000825
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 12, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.146C>T (p.P49L) alteration is located in exon 1 (coding exon 1) of the PYGB gene. This alteration results from a C to T substitution at nucleotide position 146, causing the proline (P) at amino acid position 49 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.097
D
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.65
D
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.24
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.46
D
MetaRNN
Uncertain
0.45
T
MetaSVM
Benign
-0.45
T
MutationAssessor
Benign
1.3
L
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.9
D
REVEL
Uncertain
0.46
Sift
Benign
0.19
T
Sift4G
Benign
0.26
T
Polyphen
0.0010
B
Vest4
0.54
MutPred
0.34
Loss of phosphorylation at T48 (P = 0.0546);
MVP
0.87
MPC
0.21
ClinPred
0.69
D
GERP RS
2.2
Varity_R
0.66
gMVP
0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs780809195; hg19: chr20-25228960; API