Genetic Variant PDCD1LG2:p.Lys259Thr (chr9-5563171-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025239.4(PDCD1LG2):c.776A>C(p.Lys259Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K259E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PDCD1LG2
NM_025239.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0580

Publications

0 publications found

Variant links:

Genes affected

PDCD1LG2 (HGNC:18731): (programmed cell death 1 ligand 2) Involved in negative regulation of activated T cell proliferation; negative regulation of interferon-gamma production; and negative regulation of interleukin-10 production. Predicted to be located in plasma membrane. Predicted to be active in external side of plasma membrane. Biomarker of pulmonary tuberculosis. [provided by Alliance of Genome Resources, Apr 2022]

PDCD1LG2 links:

ENSG00000286162 (HGNC:56906):

ENSG00000286162 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062424064).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025239.4. 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
	PDCD1LG2	NM_025239.4	MANE Select	c.776A>C	p.Lys259Thr	missense	Exon 6 of 7	NP_079515.2	Q9BQ51-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDCD1LG2	ENST00000397747.5	TSL:1 MANE Select	c.776A>C	p.Lys259Thr	missense	Exon 6 of 7	ENSP00000380855.3	Q9BQ51-1
PDCD1LG2	ENST00000965244.1		c.776A>C	p.Lys259Thr	missense	Exon 6 of 8	ENSP00000635303.1
PDCD1LG2	ENST00000965245.1		c.776A>C	p.Lys259Thr	missense	Exon 6 of 7	ENSP00000635304.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459714

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726268

show subpopulations

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

African (AFR)

AF:

0.0000598

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110296

Other (OTH)

AF:

0.00

AC:

AN:

60300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.59

M_CAP

Benign

0.0022

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.0

PhyloP100

0.058

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.3

REVEL

Benign

0.020

Sift

Uncertain

0.014

Sift4G

Uncertain

0.033

Polyphen

0.010

Vest4

0.20

MutPred

0.39

Loss of methylation at K259 (P = 0.0024)

MVP

0.29

MPC

0.053

ClinPred

0.38

GERP RS

0.66

Varity_R

0.048

gMVP

0.16

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over