Genetic Variant PDCD2:p.Ala74Thr (chr6-170584362-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002598.4(PDCD2):c.220G>A(p.Ala74Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000968 in 1,342,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

PDCD2
NM_002598.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00

Variant links:

Genes affected

PDCD2 (HGNC:8762): (programmed cell death 2) This gene encodes a nuclear protein expressed in a variety of tissues. Expression of this gene has been shown to be repressed by B-cell CLL/lymphoma 6 (BCL6), a transcriptional repressor required for lymph node germinal center development, suggesting that BCL6 regulates apoptosis by its effects on this protein. Alternative splicing results in multiple transcript variants and pseudogenes have been identified on chromosomes 9 and 12. [provided by RefSeq, Dec 2010]

PDCD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23761076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD2	NM_002598.4 link	c.220G>A	p.Ala74Thr	missense_variant	Exon 1 of 6	ENST00000541970.6	NP_002589.2	Q16342-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDCD2	ENST00000541970.6 link	c.220G>A	p.Ala74Thr	missense_variant	Exon 1 of 6	1	NM_002598.4	ENSP00000439467.1		Q16342-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000672

AC:

AN:

148740

Hom.:

AF XY:

0.0000116

AC XY:

AN XY:

85974

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000140

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000968

AC:

AN:

1342296

Hom.:

Cov.:

AF XY:

0.00000749

AC XY:

AN XY:

667492

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000685

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000661

Gnomad4 OTH exome

AF:

0.0000183

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.220G>A (p.A74T) alteration is located in exon 1 (coding exon 1) of the PDCD2 gene. This alteration results from a G to A substitution at nucleotide position 220, causing the alanine (A) at amino acid position 74 to be replaced by a threonine (T). 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

0.24

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.;.;.;T;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.24

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;.;.;M;.;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.7

N;N;N;N;N;.;N

REVEL

Benign

0.059

Sift

Uncertain

0.024

D;D;D;T;D;.;D

Sift4G

Benign

0.16

T;T;D;T;T;D;T

Polyphen

0.78

P;.;D;.;.;.;.

Vest4

0.32

MutPred

0.37

Gain of phosphorylation at A74 (P = 0.0226);.;Gain of phosphorylation at A74 (P = 0.0226);Gain of phosphorylation at A74 (P = 0.0226);.;Gain of phosphorylation at A74 (P = 0.0226);.;

MVP

0.45

MPC

0.11

ClinPred

0.86

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.45

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over