chr15-72202473-C-T

Variant names:

• chr15-72202473-C-T
• rs750752269
• NM_002654.6:c.1288G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002654.6(PKM):​c.1288G>A​(p.Val430Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000409 in 1,613,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: PKM NM_002654.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37820348).
• BS2: High AC in GnomAdExome4 at 63 AD gene.

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.1288G>A	p.Val430Ile	missense	Exon 9 of 11	NP_002645.3
	PKM	NM_001411081.1		c.1510G>A	p.Val504Ile	missense	Exon 10 of 12	NP_001398010.1	A0A8V8TNX9
	PKM	NM_001206798.3		c.1243G>A	p.Val415Ile	missense	Exon 9 of 11	NP_001193727.1	P14618-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKM	ENST00000335181.10	TSL:1 MANE Select	c.1288G>A	p.Val430Ile	missense	Exon 9 of 11	ENSP00000334983.5	P14618-1
	PKM	ENST00000565184.6	TSL:1	c.1412+549G>A		intron	N/A	ENSP00000455736.2	A0A804F6T5
	PKM	ENST00000568459.5	TSL:1	c.1307+549G>A		intron	N/A	ENSP00000456970.1	P14618-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248868 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1460916 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 726700

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111850

Other (OTH) AF: 0.0000994 AC: 6 AN: 60356

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

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	0.14
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.38	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.7
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.057	T
Polyphen		0.27	B
Vest4		0.27
MVP		0.83
ClinPred		0.10	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
Mutation Taster		=50/50

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: rs750752269; hg19: chr15-72494814;