1-155291858-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS2

The NM_000298.6(PKLR):c.1516G>A(p.Val506Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00547 in 1,614,046 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V506V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0056 ( 41 hom. )

Consequence

PKLR
NM_000298.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:4

Conservation

PhyloP100: 3.97

Publications

16 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: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, ClinGen
pyruvate kinase hyperactivity
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PKLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 deficiency of red cells, pyruvate kinase hyperactivity.

BP4

Computational evidence support a benign effect (MetaRNN=0.010544926).

BP6

Variant 1-155291858-C-T is Benign according to our data. Variant chr1-155291858-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235407.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

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.1516G>A	p.Val506Ile	missense	Exon 10 of 11	NP_000289.1	P30613-1
	PKLR	NM_181871.4		c.1423G>A	p.Val475Ile	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.1516G>A	p.Val506Ile	missense	Exon 10 of 11	ENSP00000339933.4	P30613-1
	PKLR	ENST00000392414.7	TSL:1	c.1423G>A	p.Val475Ile	missense	Exon 10 of 11	ENSP00000376214.3	P30613-2

Frequencies

GnomAD3 genomes

AF:

0.00413

AC:

629

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00498

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00653

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00436

AC:

1096

AN:

251476

AF XY:

0.00493

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00606

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00561

AC:

8195

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00561

AC XY:

4083

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33478

American (AMR)

AF:

0.00271

AC:

121

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00681

AC:

587

AN:

86250

European-Finnish (FIN)

AF:

0.00140

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00558

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00636

AC:

7075

AN:

1111966

Other (OTH)

AF:

0.00392

AC:

237

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

467

934

1402

1869

2336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.00413

AC:

629

AN:

152254

Hom.:

Cov.:

AF XY:

0.00394

AC XY:

293

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41558

American (AMR)

AF:

0.00536

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00499

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00653

AC:

444

AN:

68010

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

126

158

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:

0.00545

Hom.:

Bravo

AF:

0.00434

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00419

AC:

509

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00676

EpiControl

AF:

0.00747

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Pyruvate kinase deficiency of red cells (2)

PKLR-related disorder (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.067

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.022

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

0.78

PhyloP100

4.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.34

REVEL

Uncertain

0.53

Sift

Benign

0.15

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.098

MVP

0.79

MPC

0.34

ClinPred

0.0060

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.77

Mutation Taster

=75/25

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

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