6-170580003-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_002598.4(PDCD2):c.761A>G(p.Gln254Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 7.4e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PDCD2
NM_002598.4 missense, splice_region
NM_002598.4 missense, splice_region
Scores
12
4
3
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 6.14
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.981
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDCD2 | NM_002598.4 | c.761A>G | p.Gln254Arg | missense_variant, splice_region_variant | 4/6 | ENST00000541970.6 | |
PDCD2 | NM_001199462.2 | c.662A>G | p.Gln221Arg | missense_variant, splice_region_variant | 5/7 | ||
PDCD2 | NM_001363655.2 | c.761A>G | p.Gln254Arg | missense_variant, splice_region_variant | 4/6 | ||
PDCD2 | XM_047418861.1 | c.659-1033A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDCD2 | ENST00000541970.6 | c.761A>G | p.Gln254Arg | missense_variant, splice_region_variant | 4/6 | 1 | NM_002598.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33
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?
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251256Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135802
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.41e-7 AC: 1AN: 1349820Hom.: 0 Cov.: 21 AF XY: 0.00000148 AC XY: 1AN XY: 677948
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74370
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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 submitter | clinical testing | Ambry Genetics | May 06, 2022 | The c.761A>G (p.Q254R) alteration is located in exon 4 (coding exon 4) of the PDCD2 gene. This alteration results from a A to G substitution at nucleotide position 761, causing the glutamine (Q) at amino acid position 254 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D;T;T
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0326);.;Gain of MoRF binding (P = 0.0326);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at