1-155290592-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000298.6(PKLR):c.1705C>A(p.Arg569Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,605,358 control chromosomes in the GnomAD database, including 77,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10448 hom., cov: 30)

Exomes 𝑓: 0.29 ( 66956 hom. )

Consequence

PKLR
NM_000298.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.08

Publications

53 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 1-155290592-G-T is Benign according to our data. Variant chr1-155290592-G-T is described in ClinVar as Benign. ClinVar VariationId is 255798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.08 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	NM_000298.6	MANE Select	c.1705C>A	p.Arg569Arg	synonymous	Exon 11 of 11	NP_000289.1
	PKLR	NM_181871.4		c.1612C>A	p.Arg538Arg	synonymous	Exon 11 of 11	NP_870986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	ENST00000342741.6	TSL:1 MANE Select	c.1705C>A	p.Arg569Arg	synonymous	Exon 11 of 11	ENSP00000339933.4
	PKLR	ENST00000392414.7	TSL:1	c.1612C>A	p.Arg538Arg	synonymous	Exon 11 of 11	ENSP00000376214.3

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

53260

AN:

151634

Hom.:

10413

Cov.:

show subpopulations

Gnomad AFR

AF:

0.490

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.333

Gnomad ASJ

AF:

0.211

Gnomad EAS

AF:

0.702

Gnomad SAS

AF:

0.341

Gnomad FIN

AF:

0.318

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.262

Gnomad OTH

AF:

0.334

GnomAD2 exomes

AF:

0.337

AC:

84394

AN:

250236

AF XY:

0.326

show subpopulations

Gnomad AFR exome

AF:

0.499

Gnomad AMR exome

AF:

0.411

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.702

Gnomad FIN exome

AF:

0.311

Gnomad NFE exome

AF:

0.251

Gnomad OTH exome

AF:

0.300

GnomAD4 exome

AF:

0.289

AC:

419413

AN:

1453606

Hom.:

66956

Cov.:

AF XY:

0.287

AC XY:

207575

AN XY:

723622

show subpopulations

African (AFR)

AF:

0.496

AC:

16506

AN:

33278

American (AMR)

AF:

0.406

AC:

18114

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

5779

AN:

26088

East Asian (EAS)

AF:

0.724

AC:

28714

AN:

39636

South Asian (SAS)

AF:

0.328

AC:

28237

AN:

86026

European-Finnish (FIN)

AF:

0.304

AC:

16184

AN:

53170

Middle Eastern (MID)

AF:

0.201

AC:

1156

AN:

5760

European-Non Finnish (NFE)

AF:

0.259

AC:

286481

AN:

1104918

Other (OTH)

AF:

0.304

AC:

18242

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

13027

26054

39082

52109

65136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10118

20236

30354

40472

50590

<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:

0.352

AC:

53347

AN:

151752

Hom.:

10448

Cov.:

AF XY:

0.354

AC XY:

26252

AN XY:

74134

show subpopulations

African (AFR)

AF:

0.491

AC:

20284

AN:

41316

American (AMR)

AF:

0.334

AC:

5096

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.211

AC:

730

AN:

3466

East Asian (EAS)

AF:

0.701

AC:

3613

AN:

5152

South Asian (SAS)

AF:

0.341

AC:

1640

AN:

4810

European-Finnish (FIN)

AF:

0.318

AC:

3346

AN:

10538

Middle Eastern (MID)

AF:

0.233

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.262

AC:

17777

AN:

67916

Other (OTH)

AF:

0.330

AC:

693

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1599

3198

4796

6395

7994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.269

Hom.:

10588

Bravo

AF:

0.364

Asia WGS

AF:

0.540

AC:

1880

AN:

3478

EpiCase

AF:

0.246

EpiControl

AF:

0.238

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 21, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg569Arg variant in PKLP is classified as benign because it has been identified in 70% (13958/19872) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1, BP7.

not provided

Benign:4

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pyruvate kinase deficiency of red cells

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.9

(source)

DANN

Benign

0.85

PhyloP100

3.1

Mutation Taster

=99/1

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over