Genetic Variant PDCD1:c.437-115G>A (chr2-241852468-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005018.3(PDCD1):c.437-115G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 1,149,474 control chromosomes in the GnomAD database, including 6,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 972 hom., cov: 33)

Exomes 𝑓: 0.039 ( 5187 hom. )

Consequence

PDCD1
NM_005018.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.98

Variant links:

Genes affected

PDCD1 (HGNC:8760): (programmed cell death 1) Programmed cell death protein 1 (PDCD1) is an immune-inhibitory receptor expressed in activated T cells; it is involved in the regulation of T-cell functions, including those of effector CD8+ T cells. In addition, this protein can also promote the differentiation of CD4+ T cells into T regulatory cells. PDCD1 is expressed in many types of tumors including melanomas, and has demonstrated to play a role in anti-tumor immunity. Moreover, this protein has been shown to be involved in safeguarding against autoimmunity, however, it can also contribute to the inhibition of effective anti-tumor and anti-microbial immunity. [provided by RefSeq, Aug 2020]

PDCD1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 2-241852468-C-T is Benign according to our data. Variant chr2-241852468-C-T is described in ClinVar as [Benign]. Clinvar id is 1233776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD1	NM_005018.3 link	c.437-115G>A		intron_variant	Intron 2 of 4	ENST00000334409.10	NP_005009.2	Q15116A0A0M3M0G7
PDCD1	XM_006712573.3 link	c.437-115G>A		intron_variant	Intron 2 of 3		XP_006712636.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PDCD1	ENST00000334409.10 link	c.437-115G>A	intron_variant	Intron 2 of 4	1	NM_005018.3	ENSP00000335062.5	Q15116
PDCD1	ENST00000343705.3 link	c.265+153G>A	intron_variant	Intron 1 of 2	1		ENSP00000340808.4	H0Y2W6
PDCD1	ENST00000418831.1 link	n.201-115G>A	intron_variant	Intron 2 of 4	1		ENSP00000390296.1	E7ER21

Frequencies

GnomAD3 genomes

AF:

0.0486

AC:

7383

AN:

151960

Hom.:

964

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00960

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.173

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.474

Gnomad SAS

AF:

0.0765

Gnomad FIN

AF:

0.0534

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.0576

GnomAD4 exome

AF:

0.0385

AC:

38421

AN:

997396

Hom.:

5187

Cov.:

AF XY:

0.0387

AC XY:

19247

AN XY:

497712

show subpopulations

Gnomad4 AFR exome

AF:

0.00742

Gnomad4 AMR exome

AF:

0.232

Gnomad4 ASJ exome

AF:

0.0135

Gnomad4 EAS exome

AF:

0.481

Gnomad4 SAS exome

AF:

0.0621

Gnomad4 FIN exome

AF:

0.0503

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.0447

GnomAD4 genome

AF:

0.0487

AC:

7405

AN:

152078

Hom.:

972

Cov.:

AF XY:

0.0568

AC XY:

4226

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00957

Gnomad4 AMR

AF:

0.174

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.474

Gnomad4 SAS

AF:

0.0767

Gnomad4 FIN

AF:

0.0534

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.0617

Alfa

AF:

0.00898

Hom.:

Bravo

AF:

0.0586

Asia WGS

AF:

0.241

AC:

837

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.0

DANN

Benign

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over