NM_002598.4:c.728A>G

Variant names:

• chr6-170580036-T-C
• rs1302531250
• NM_002598.4:c.728A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002598.4(PDCD2):​c.728A>G​(p.Lys243Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,776 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDCD2 NM_002598.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17949727).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002598.4. 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
	PDCD2	NM_002598.4	MANE Select	c.728A>G	p.Lys243Arg	missense	Exon 4 of 6	NP_002589.2
	PDCD2	NM_001199462.2		c.629A>G	p.Lys210Arg	missense	Exon 5 of 7	NP_001186391.1	Q16342-3
	PDCD2	NM_001363655.2		c.728A>G	p.Lys243Arg	missense	Exon 4 of 6	NP_001350584.1	F5H4V9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD2	ENST00000541970.6	TSL:1 MANE Select	c.728A>G	p.Lys243Arg	missense	Exon 4 of 6	ENSP00000439467.1	Q16342-1
	PDCD2	ENST00000392090.6	TSL:1	c.629A>G	p.Lys210Arg	missense	Exon 5 of 7	ENSP00000375940.2	Q16342-3
	PDCD2	ENST00000542896.5	TSL:2	c.728A>G	p.Lys243Arg	missense	Exon 4 of 6	ENSP00000439914.1	F5H4V9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251268 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457776 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725542

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

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108428

Other (OTH) AF: 0.00 AC: 0 AN: 60272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

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	0.074
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.066
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.9
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.083
Sift	Benign	0.15	T
Sift4G	Benign	0.24	T
Polyphen		0.097	B
Vest4		0.082
MutPred		0.52		Loss of methylation at K243 (P = 6e-04)
MVP		0.22
MPC		0.081
ClinPred		0.42	T
GERP RS		5.6
Varity_R		0.094
gMVP		0.25
Mutation Taster		=90/10	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: rs1302531250; hg19: chr6-170889124;