rs553211441

Variant names:

• chr17-50108191-G-A
• rs553211441
• NM_002611.5:c.721G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-50108191-G-A
• chr17-50108191-G-T

Variant summary

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

The NM_002611.5(PDK2):​c.721G>A​(p.Val241Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,598,128 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PDK2 NM_002611.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.05
• Publications: 0 publications found

Genes affected

PDK2 (HGNC:8810): (pyruvate dehydrogenase kinase 2) This gene encodes a member of the pyruvate dehydrogenase kinase family. The encoded protein phosphorylates pyruvate dehydrogenase, down-regulating the activity of the mitochondrial pyruvate dehydrogenase complex. Overexpression of this gene may play a role in both cancer and diabetes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

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=0.32776612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK2	NM_002611.5	c.721G>A	p.Val241Ile	missense_variant	Exon 7 of 11	ENST00000503176.6	NP_002602.2
PDK2	NM_001199898.2	c.529G>A	p.Val177Ile	missense_variant	Exon 8 of 12		NP_001186827.1
PDK2	NM_001199899.2	c.529G>A	p.Val177Ile	missense_variant	Exon 7 of 11		NP_001186828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK2	ENST00000503176.6	c.721G>A	p.Val241Ile	missense_variant	Exon 7 of 11	1	NM_002611.5	ENSP00000420927.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000177 AC: 4 AN: 226460 AF XY: 0.0000329

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000581

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000997

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000249 AC: 36 AN: 1445826 Hom.: 0 Cov.: 31 AF XY: 0.0000223 AC XY: 16 AN XY: 717578

African (AFR) AF: 0.0000300 AC: 1 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 42590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25684

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39432

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000299 AC: 33 AN: 1103050

Other (OTH) AF: 0.00 AC: 0 AN: 59840

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74476

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.721G>A (p.V241I) alteration is located in exon 7 (coding exon 7) of the PDK2 gene. This alteration results from a G to A substitution at nucleotide position 721, causing the valine (V) at amino acid position 241 to be replaced by an isoleucine (I). 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	0.16
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.41	.;N;.;.;.
PhyloP100		8.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.93	N;N;N;.;N
REVEL	Benign	0.20
Sift	Benign	0.084	T;T;T;.;T
Sift4G	Benign	0.098	T;T;T;T;T
Polyphen		0.58	.;P;.;.;.
Vest4		0.32
MutPred		0.77		.;Loss of catalytic residue at V241 (P = 0.0675);.;.;.;
MVP		0.71
MPC		0.99
ClinPred		0.43	T
GERP RS		4.6
Varity_R		0.31
gMVP		0.45
Mutation Taster		=67/33	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: rs553211441; hg19: chr17-48185555;