Genetic Variant PKM:p.Asn146Asn (chr15-72209800-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002654.6(PKM):c.438C>T(p.Asn146Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0716 in 1,613,704 control chromosomes in the GnomAD database, including 4,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 325 hom., cov: 31)

Exomes 𝑓: 0.073 ( 4253 hom. )

Consequence

PKM
NM_002654.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.607

Publications

12 publications found

Variant links:

Genes affected

PKM (HGNC:9021): (pyruvate kinase M1/2) This gene encodes a protein involved in glycolysis. The encoded protein is a pyruvate kinase that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate to ADP, generating ATP and pyruvate. This protein has been shown to interact with thyroid hormone and may mediate cellular metabolic effects induced by thyroid hormones. This protein has been found to bind Opa protein, a bacterial outer membrane protein involved in gonococcal adherence to and invasion of human cells, suggesting a role of this protein in bacterial pathogenesis. Several alternatively spliced transcript variants encoding a few distinct isoforms have been reported. [provided by RefSeq, May 2011]

PKM links:

ENSG00000303314 (HGNC:):

ENSG00000303314 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 15-72209800-G-A is Benign according to our data. Variant chr15-72209800-G-A is described in ClinVar as Benign. ClinVar VariationId is 403311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.607 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKM	NM_002654.6 link	c.438C>T	p.Asn146Asn	synonymous_variant	Exon 5 of 11	ENST00000335181.10	NP_002645.3	P14618-1V9HWB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKM	ENST00000335181.10 link	c.438C>T	p.Asn146Asn	synonymous_variant	Exon 5 of 11	1	NM_002654.6	ENSP00000334983.5		P14618-1

Frequencies

GnomAD3 genomes

AF:

0.0604

AC:

9178

AN:

151930

Hom.:

324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0327

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0642

Gnomad ASJ

AF:

0.0842

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.0855

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0780

Gnomad OTH

AF:

0.0709

GnomAD2 exomes

AF:

0.0610

AC:

15331

AN:

251492

AF XY:

0.0613

show subpopulations

Gnomad AFR exome

AF:

0.0290

Gnomad AMR exome

AF:

0.0409

Gnomad ASJ exome

AF:

0.0863

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.0866

Gnomad NFE exome

AF:

0.0817

Gnomad OTH exome

AF:

0.0790

GnomAD4 exome

AF:

0.0727

AC:

106333

AN:

1461656

Hom.:

4253

Cov.:

AF XY:

0.0713

AC XY:

51872

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.0329

AC:

1100

AN:

33476

American (AMR)

AF:

0.0432

AC:

1930

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0828

AC:

2163

AN:

26134

East Asian (EAS)

AF:

0.000378

AC:

AN:

39700

South Asian (SAS)

AF:

0.0301

AC:

2595

AN:

86258

European-Finnish (FIN)

AF:

0.0893

AC:

4769

AN:

53418

Middle Eastern (MID)

AF:

0.0827

AC:

477

AN:

5768

European-Non Finnish (NFE)

AF:

0.0800

AC:

88938

AN:

1111786

Other (OTH)

AF:

0.0720

AC:

4346

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

5285

10570

15855

21140

26425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3188

6376

9564

12752

15940

<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:

0.0604

AC:

9183

AN:

152048

Hom.:

325

Cov.:

AF XY:

0.0599

AC XY:

4450

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.0327

AC:

1355

AN:

41478

American (AMR)

AF:

0.0641

AC:

979

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0842

AC:

292

AN:

3466

East Asian (EAS)

AF:

0.000774

AC:

AN:

5168

South Asian (SAS)

AF:

0.0293

AC:

141

AN:

4820

European-Finnish (FIN)

AF:

0.0855

AC:

902

AN:

10544

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0780

AC:

5303

AN:

67986

Other (OTH)

AF:

0.0697

AC:

147

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

433

866

1299

1732

2165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0734

Hom.:

179

Bravo

AF:

0.0577

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0803

EpiControl

AF:

0.0840

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided

Benign:1

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

-0.75

CADD

Benign

0.081

(source)

DANN

Benign

0.56

PhyloP100

-0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over