rs118204083

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_000298.6(PKLR):c.487C>T(p.Arg163Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PKLR
NM_000298.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 3.28

Publications

6 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: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
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_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000298.6

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKLR	NM_000298.6 link	c.487C>T	p.Arg163Cys	missense_variant	Exon 4 of 11	ENST00000342741.6	NP_000289.1	P30613-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PKLR	ENST00000342741.6 link	c.487C>T	p.Arg163Cys	missense_variant	Exon 4 of 11	1	NM_000298.6	ENSP00000339933.4	P30613-1
PKLR	ENST00000392414.7 link	c.394C>T	p.Arg132Cys	missense_variant	Exon 4 of 11	1		ENSP00000376214.3	P30613-2
PKLR	ENST00000434082.3 link	c.295C>T	p.Arg99Cys	missense_variant	Exon 4 of 5	5		ENSP00000398037.3	F8W6W2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1456230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724102

African (AFR)

AF:

0.00

AC:

AN:

33342

American (AMR)

AF:

0.00

AC:

AN:

43466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25970

East Asian (EAS)

AF:

0.00

AC:

AN:

39468

South Asian (SAS)

AF:

0.00

AC:

AN:

85636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109604

Other (OTH)

AF:

0.00

AC:

AN:

60122

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pyruvate kinase deficiency of red cells

Pathogenic:1

May 01, 1991

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Mar 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg163 amino acid residue in PKLR. Other variant(s) that disrupt this residue have been observed in individuals with PKLR-related conditions (PMID: 2018831, 19085939), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects PKLR function (PMID: 2018831). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1506). This variant is also known as PK Linz variant, a C to T base exchange at position 394 . This missense change has been observed in individual(s) with pyruvate kinase deficiency (PMID: 2018831; Invitae). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 163 of the PKLR protein (p.Arg163Cys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

.;.;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;.;.

PhyloP100

3.3

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-7.0

D;D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.90

MutPred

0.98

Loss of disorder (P = 0.0393);.;.;

MVP

0.99

MPC

1.5

ClinPred

1.0

GERP RS

4.1

Varity_R

0.96

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over