9-5563171-A-C

Position:

• chr9-5563171-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PDCD1LG2 NM_025239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0580

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]

ENSG00000286162 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062424064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDCD1LG2	NM_025239.4	c.776A>C	p.Lys259Thr	missense_variant	6/7	ENST00000397747.5	NP_079515.2
PDCD1LG2	XM_005251600.4	c.776A>C	p.Lys259Thr	missense_variant	6/7		XP_005251657.1
LOC124902114	XR_007061406.1	n.162-38542T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDCD1LG2	ENST00000397747.5	c.776A>C	p.Lys259Thr	missense_variant	6/7	1	NM_025239.4	ENSP00000380855.3
ENSG00000286162	ENST00000661858.1	n.183-38542T>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459714 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726268

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.776A>C (p.K259T) alteration is located in exon 6 (coding exon 5) of the PDCD1LG2 gene. This alteration results from a A to C substitution at nucleotide position 776, causing the lysine (K) at amino acid position 259 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	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.020
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.033	D
Polyphen		0.010	B
Vest4		0.20
MutPred		0.39		Loss of methylation at K259 (P = 0.0024);
MVP		0.29
MPC		0.053
ClinPred		0.38	T
GERP RS		0.66
Varity_R		0.048
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs1816599755; hg19: chr9-5563171;