15-72208751-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002654.6(PKM):​c.706G>A​(p.Asp236Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,614,182 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000065 ( 1 hom. )

Consequence

PKM
NM_002654.6 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.14
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.08628175).
BS2
High AC in GnomAdExome4 at 95 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PKMNM_002654.6 linkc.706G>A p.Asp236Asn missense_variant 6/11 ENST00000335181.10 NP_002645.3 P14618-1V9HWB8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PKMENST00000335181.10 linkc.706G>A p.Asp236Asn missense_variant 6/111 NM_002654.6 ENSP00000334983.5 P14618-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152172
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000131
AC:
33
AN:
251494
Hom.:
0
AF XY:
0.000177
AC XY:
24
AN XY:
135920
show subpopulations
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:
0.000849
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000439
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000650
AC:
95
AN:
1461892
Hom.:
1
Cov.:
32
AF XY:
0.0000839
AC XY:
61
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000858
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152290
Hom.:
0
Cov.:
31
AF XY:
0.0000537
AC XY:
4
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.000115
AC:
14

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 09, 2021The c.706G>A (p.D236N) alteration is located in exon 6 (coding exon 5) of the PKM gene. This alteration results from a G to A substitution at nucleotide position 706, causing the aspartic acid (D) at amino acid position 236 to be replaced by an asparagine (N). 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
0.090
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.45
.;.;.;.;T;T;.;.;T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.16
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.87
D;D;D;.;D;D;.;.;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.086
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
-0.20
.;N;.;N;N;.;N;N;.
PrimateAI
Benign
0.42
T
PROVEAN
Benign
0.050
N;N;.;N;N;N;N;N;N
REVEL
Benign
0.064
Sift
Benign
0.36
T;T;.;T;T;T;T;T;T
Sift4G
Benign
0.37
T;T;T;T;T;T;T;T;T
Polyphen
0.0, 0.0020, 0.0010
.;B;B;B;B;.;B;B;.
Vest4
0.093
MutPred
0.51
.;Loss of catalytic residue at D236 (P = 0.0922);.;Loss of catalytic residue at D236 (P = 0.0922);Loss of catalytic residue at D236 (P = 0.0922);.;Loss of catalytic residue at D236 (P = 0.0922);Loss of catalytic residue at D236 (P = 0.0922);Loss of catalytic residue at D236 (P = 0.0922);
MVP
0.77
MPC
0.62
ClinPred
0.036
T
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.23
gMVP
0.52

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs548240358; hg19: chr15-72501092; API