15-72208777-T-C

Position:

• chr15-72208777-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002654.6(PKM):​c.680A>G​(p.Gln227Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PKM NM_002654.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKM	NM_002654.6	c.680A>G	p.Gln227Arg	missense_variant	6/11	ENST00000335181.10	NP_002645.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKM	ENST00000335181.10	c.680A>G	p.Gln227Arg	missense_variant	6/11	1	NM_002654.6	ENSP00000334983.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251488 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2024

The c.680A>G (p.Q227R) alteration is located in exon 6 (coding exon 5) of the PKM gene. This alteration results from a A to G substitution at nucleotide position 680, causing the glutamine (Q) at amino acid position 227 to be replaced by an arginine (R). 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	Benign	0.15
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;.;.;.;D;T;.;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;D;.;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.015	.;N;.;N;N;.;N;N;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.97	N;N;.;N;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.29	T;T;.;T;T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T;T;T;T;T
Polyphen		0.0020, 0.010, 0.0070	.;B;B;B;B;.;B;B;.
Vest4		0.51
MutPred		0.26		.;Loss of methylation at K230 (P = 0.0683);.;Loss of methylation at K230 (P = 0.0683);Loss of methylation at K230 (P = 0.0683);.;Loss of methylation at K230 (P = 0.0683);Loss of methylation at K230 (P = 0.0683);Loss of methylation at K230 (P = 0.0683);
MVP		0.93
MPC		0.69
ClinPred		0.48	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs777291292; hg19: chr15-72501118;