PKLR p.Glu538Asp

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBS2_Supporting

The NM_000298.6(PKLR):c.1614A>T(p.Glu538Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,613,966 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00029 ( 2 hom. )

Consequence

PKLR
NM_000298.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: -0.264

Publications

5 publications found

Variant links:

Genes affected

PKLR (HGNC:9020): (pyruvate kinase L/R) The protein encoded by this gene is a pyruvate kinase that catalyzes the transphosphorylation of phohsphoenolpyruvate into pyruvate and ATP, which is the rate-limiting step of glycolysis. Defects in this enzyme, due to gene mutations or genetic variations, are the common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA or HNSHA). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PKLR Gene-Disease associations (from GenCC):

pyruvate kinase deficiency of red cells
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
pyruvate kinase hyperactivity
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PKLR links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000298.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000298.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.98056 (below the threshold of 3.09). Trascript score misZ: 1.5963 (below the threshold of 3.09). GenCC associations: The gene is linked to pyruvate kinase hyperactivity, pyruvate kinase deficiency of red cells.

BP4

Computational evidence support a benign effect (MetaRNN=0.025737584).

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR 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_000298.6. 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
	PKLR	NM_000298.6	MANE Select	c.1614A>T	p.Glu538Asp	missense	Exon 10 of 11	NP_000289.1	P30613-1
	PKLR	NM_181871.4		c.1521A>T	p.Glu507Asp	missense	Exon 10 of 11	NP_870986.1	P30613-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	ENST00000342741.6	TSL:1 MANE Select	c.1614A>T	p.Glu538Asp	missense	Exon 10 of 11	ENSP00000339933.4	P30613-1
	PKLR	ENST00000392414.7	TSL:1	c.1521A>T	p.Glu507Asp	missense	Exon 10 of 11	ENSP00000376214.3	P30613-2

Frequencies

GnomAD3 genomes

AF:

0.000520

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000398

AC:

100

AN:

251484

AF XY:

0.000375

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000292

AC:

427

AN:

1461846

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

202

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.000715

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00200

AC:

107

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000237

AC:

264

AN:

1111976

Other (OTH)

AF:

0.000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000519

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41504

American (AMR)

AF:

0.000916

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

67956

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000158

Hom.:

Bravo

AF:

0.000329

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Pyruvate kinase deficiency of red cells;C1863224:Pyruvate kinase hyperactivity (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.72

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.23

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.026

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

0.36

PhyloP100

-0.26

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.71

REVEL

Uncertain

0.55

Sift

Benign

0.40

Sift4G

Benign

0.55

Varity_R

0.30

gMVP

0.89

Mutation Taster

=90/10

polymorphism

(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

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

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