Genetic Variant PDCD1LG2:p.Gln91Glu (chr9-5534960-C-G) – 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.271C>G(p.Gln91Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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)

Consequence

PDCD1LG2
NM_025239.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.647

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:):

ENSG00000286162 links:

INCR1 (HGNC:56906):

INCR1 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=0.06717208).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD1LG2	NM_025239.4 link	c.271C>G	p.Gln91Glu	missense_variant	Exon 3 of 7	ENST00000397747.5	NP_079515.2	Q9BQ51-1
PDCD1LG2	XM_005251600.4 link	c.271C>G	p.Gln91Glu	missense_variant	Exon 3 of 7		XP_005251657.1
INCR1	XR_007061406.1 link	n.162-10331G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDCD1LG2	ENST00000397747.5 link	c.271C>G	p.Gln91Glu	missense_variant	Exon 3 of 7	1	NM_025239.4	ENSP00000380855.3		Q9BQ51-1
ENSG00000286162	ENST00000661858.1 link	n.183-10331G>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.271C>G (p.Q91E) alteration is located in exon 3 (coding exon 2) of the PDCD1LG2 gene. This alteration results from a C to G substitution at nucleotide position 271, causing the glutamine (Q) at amino acid position 91 to be replaced by a glutamic acid (E). 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

0.074

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.3

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.050

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.70

M_CAP

Benign

0.0048

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

PhyloP100

-0.65

PrimateAI

Benign

0.20

PROVEAN

Benign

0.010

REVEL

Benign

0.022

Sift

Benign

0.082

Sift4G

Benign

0.40

Polyphen

0.24

Vest4

0.093

MutPred

0.47

Gain of catalytic residue at Q91 (P = 0.0943);

MVP

0.30

MPC

0.046

ClinPred

0.076

GERP RS

-1.1

Varity_R

0.15

gMVP

0.37

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over