2-241851407-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005018.3(PDCD1):c.628-110A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,114,208 control chromosomes in the GnomAD database, including 204,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28377 hom., cov: 32)
  • Exomes 𝑓: 0.60 (176040 hom.)
• Consequence: PDCD1 NM_005018.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0790

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-241851407-T-C is Benign according to our data. Variant chr2-241851407-T-C is described in ClinVar as [Benign]. Clinvar id is 1257448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDCD1	NM_005018.3	c.628-110A>G		intron_variant		ENST00000334409.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDCD1	ENST00000334409.10	c.628-110A>G		intron_variant		1	NM_005018.3	P1
PDCD1	ENST00000343705.3	c.302-110A>G		intron_variant		1
PDCD1	ENST00000418831.1	c.*191-110A>G		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92354 AN: 151926 Hom.: 28338 Cov.: 32

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.755

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.601

GnomAD4 exome AF: 0.602 AC: 579292 AN: 962164 Hom.: 176040 AF XY: 0.606 AC XY: 292451 AN XY: 482462

Gnomad4 AFR exome AF: 0.575

Gnomad4 AMR exome AF: 0.626

Gnomad4 ASJ exome AF: 0.622

Gnomad4 EAS exome AF: 0.700

Gnomad4 SAS exome AF: 0.744

Gnomad4 FIN exome AF: 0.700

Gnomad4 NFE exome AF: 0.579

Gnomad4 OTH exome AF: 0.607

GnomAD4 genome AF: 0.608 AC: 92448 AN: 152044 Hom.: 28377 Cov.: 32 AF XY: 0.620 AC XY: 46068 AN XY: 74320

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.641

Gnomad4 ASJ AF: 0.616

Gnomad4 EAS AF: 0.726

Gnomad4 SAS AF: 0.756

Gnomad4 FIN AF: 0.716

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.606

Alfa AF: 0.592 Hom.: 3336

Bravo AF: 0.597

Asia WGS AF: 0.737 AC: 2560 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	4.9
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6705653; hg19: chr2-242793559; COSMIC: COSV57690925;