NM_002654.6:c.547C>T

Variant names:

• chr15-72209691-G-A
• rs957923042
• NM_002654.6:c.547C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002654.6(PKM):​c.547C>T​(p.Leu183Phe) variant causes a missense change. 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: 30)
• Consequence: PKM NM_002654.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKM	NM_002654.6	c.547C>T	p.Leu183Phe	missense_variant	Exon 5 of 11	ENST00000335181.10	NP_002645.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKM	ENST00000335181.10	c.547C>T	p.Leu183Phe	missense_variant	Exon 5 of 11	1	NM_002654.6	ENSP00000334983.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.547C>T (p.L183F) alteration is located in exon 5 (coding exon 4) of the PKM gene. This alteration results from a C to T substitution at nucleotide position 547, causing the leucine (L) at amino acid position 183 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;.;.;D;.;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;.;.;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	.;M;.;M;M;M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.31	T;T;.;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T
Polyphen		1.0, 0.99	.;D;D;D;D;D;D;.
Vest4		0.82
MutPred		0.68		.;Gain of ubiquitination at K188 (P = 0.0954);.;Gain of ubiquitination at K188 (P = 0.0954);Gain of ubiquitination at K188 (P = 0.0954);Gain of ubiquitination at K188 (P = 0.0954);Gain of ubiquitination at K188 (P = 0.0954);Gain of ubiquitination at K188 (P = 0.0954);
MVP		0.96
MPC		1.6
ClinPred		0.91	D
GERP RS		5.5
Varity_R		0.61
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs957923042; hg19: chr15-72502032; COSMIC: COSV100065079; COSMIC: COSV100065079;