NM_000298.6:c.1705C>A

Variant names:

• chr1-155290592-G-T
• rs1052176
• NM_000298.6:c.1705C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.08
• Publications: 53 publications found

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)

ACMG classification

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

Sel.	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	P30613-1
	PKLR	NM_181871.4		c.1612C>A	p.Arg538Arg	synonymous	Exon 11 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.1705C>A	p.Arg569Arg	synonymous	Exon 11 of 11	ENSP00000339933.4	P30613-1
	PKLR	ENST00000392414.7	TSL:1	c.1612C>A	p.Arg538Arg	synonymous	Exon 11 of 11	ENSP00000376214.3	P30613-2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53260 AN: 151634 Hom.: 10413 Cov.: 30

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

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.: 30 AF XY: 0.287 AC XY: 207575 AN XY: 723622

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

GnomAD4 genome AF: 0.352 AC: 53347 AN: 151752 Hom.: 10448 Cov.: 30 AF XY: 0.354 AC XY: 26252 AN XY: 74134

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: 68 AN: 292

European-Non Finnish (NFE) AF: 0.262 AC: 17777 AN: 67916

Other (OTH) AF: 0.330 AC: 693 AN: 2098

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Pyruvate kinase deficiency of red cells (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.9
DANN	Benign	0.85
PhyloP100		3.1
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1052176; hg19: chr1-155260383; COSMIC: COSV100712848; COSMIC: COSV100712848;