chr1-155295386-A-G

Variant names:

• chr1-155295386-A-G
• rs2071053
• NM_000298.6:c.507+51T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000298.6(PKLR):​c.507+51T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,612,016 control chromosomes in the GnomAD database, including 84,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13507 hom., cov: 33)
  • Exomes 𝑓: 0.29 (70621 hom.)
• Consequence: PKLR NM_000298.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.49
• Publications: 18 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: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
• pyruvate kinase hyperactivity

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-155295386-A-G is Benign according to our data. Variant chr1-155295386-A-G is described in ClinVar as Benign. ClinVar VariationId is 1280101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKLR	NM_000298.6	c.507+51T>C		intron_variant	Intron 4 of 10	ENST00000342741.6	NP_000289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6	c.507+51T>C		intron_variant	Intron 4 of 10	1	NM_000298.6	ENSP00000339933.4
PKLR	ENST00000392414.7	c.414+51T>C		intron_variant	Intron 4 of 10	1		ENSP00000376214.3
PKLR	ENST00000434082.3	c.315+51T>C		intron_variant	Intron 4 of 4	5		ENSP00000398037.3

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58981 AN: 151914 Hom.: 13456 Cov.: 33

Gnomad AFR AF: 0.614

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.363

GnomAD2 exomes AF: 0.348 AC: 83521 AN: 240092 AF XY: 0.335

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.418

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.703

Gnomad FIN exome AF: 0.316

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.295 AC: 430522 AN: 1459986 Hom.: 70621 Cov.: 39 AF XY: 0.292 AC XY: 212366 AN XY: 726308

African (AFR) AF: 0.621 AC: 20759 AN: 33454

American (AMR) AF: 0.413 AC: 18335 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5817 AN: 26098

East Asian (EAS) AF: 0.725 AC: 28729 AN: 39626

South Asian (SAS) AF: 0.329 AC: 28324 AN: 86206

European-Finnish (FIN) AF: 0.308 AC: 16321 AN: 52942

Middle Eastern (MID) AF: 0.208 AC: 1198 AN: 5760

European-Non Finnish (NFE) AF: 0.263 AC: 292106 AN: 1111202

Other (OTH) AF: 0.314 AC: 18933 AN: 60288

GnomAD4 genome AF: 0.389 AC: 59083 AN: 152030 Hom.: 13507 Cov.: 33 AF XY: 0.390 AC XY: 28953 AN XY: 74330

African (AFR) AF: 0.614 AC: 25480 AN: 41492

American (AMR) AF: 0.347 AC: 5302 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 733 AN: 3470

East Asian (EAS) AF: 0.701 AC: 3607 AN: 5142

South Asian (SAS) AF: 0.342 AC: 1649 AN: 4818

European-Finnish (FIN) AF: 0.323 AC: 3417 AN: 10588

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 17967 AN: 67904

Other (OTH) AF: 0.359 AC: 757 AN: 2110

Alfa AF: 0.218 Hom.: 716

Bravo AF: 0.405

Asia WGS AF: 0.546 AC: 1898 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.017
DANN	Benign	0.12
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs2071053; hg19: chr1-155265177; COSMIC: COSV61362644;