chr15-72208778-G-T

Variant names:

• chr15-72208778-G-T
• rs746775723
• NM_002654.6:c.679C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002654.6(PKM):​c.679C>A​(p.Gln227Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q227R) has been classified 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: 5.28
• Publications: 1 publications found

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]

ENSG00000303314 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3678621).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002654.6. 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
	PKM	NM_002654.6	MANE Select	c.679C>A	p.Gln227Lys	missense	Exon 6 of 11	NP_002645.3
	PKM	NM_001206796.3		c.901C>A	p.Gln301Lys	missense	Exon 7 of 12	NP_001193725.1	A0A804F729
	PKM	NM_001411081.1		c.901C>A	p.Gln301Lys	missense	Exon 7 of 12	NP_001398010.1	A0A8V8TNX9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKM	ENST00000335181.10	TSL:1 MANE Select	c.679C>A	p.Gln227Lys	missense	Exon 6 of 11	ENSP00000334983.5	P14618-1
	PKM	ENST00000565184.6	TSL:1	c.784C>A	p.Gln262Lys	missense	Exon 6 of 11	ENSP00000455736.2	A0A804F6T5
	PKM	ENST00000568459.5	TSL:1	c.679C>A	p.Gln227Lys	missense	Exon 6 of 11	ENSP00000456970.1	P14618-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251484 AF XY: 0.00

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 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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	0.11	N
PhyloP100		5.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.36	N
REVEL	Uncertain	0.53
Sift	Benign	0.58	T
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.26
MutPred		0.34		Gain of ubiquitination at Q227 (P = 0.0592)
MVP		0.80
MPC		0.81
ClinPred		0.22	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.57
Mutation Taster		=56/44	polymorphism

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: rs746775723; hg19: chr15-72501119;