2-241852468-C-T

Variant names:

• chr2-241852468-C-T
• rs34819629
• NM_005018.3:c.437-115G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.98
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005018.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD1	NM_005018.3	MANE Select	c.437-115G>A		intron	N/A	NP_005009.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD1	ENST00000334409.10	TSL:1 MANE Select	c.437-115G>A		intron	N/A	ENSP00000335062.5
	PDCD1	ENST00000343705.4	TSL:1	c.436+153G>A		intron	N/A	ENSP00000340808.4
	PDCD1	ENST00000418831.1	TSL:1	n.201-115G>A		intron	N/A	ENSP00000390296.1

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7383 AN: 151960 Hom.: 964 Cov.: 33

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.: 13 AF XY: 0.0387 AC XY: 19247 AN XY: 497712

African (AFR) AF: 0.00742 AC: 171 AN: 23036

American (AMR) AF: 0.232 AC: 5313 AN: 22856

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 238 AN: 17662

East Asian (EAS) AF: 0.481 AC: 16505 AN: 34312

South Asian (SAS) AF: 0.0621 AC: 3705 AN: 59658

European-Finnish (FIN) AF: 0.0503 AC: 2094 AN: 41630

Middle Eastern (MID) AF: 0.00682 AC: 21 AN: 3078

European-Non Finnish (NFE) AF: 0.0112 AC: 8406 AN: 751176

Other (OTH) AF: 0.0447 AC: 1968 AN: 43988

GnomAD4 genome AF: 0.0487 AC: 7405 AN: 152078 Hom.: 972 Cov.: 33 AF XY: 0.0568 AC XY: 4226 AN XY: 74338

African (AFR) AF: 0.00957 AC: 397 AN: 41490

American (AMR) AF: 0.174 AC: 2660 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3468

East Asian (EAS) AF: 0.474 AC: 2445 AN: 5156

South Asian (SAS) AF: 0.0767 AC: 370 AN: 4822

European-Finnish (FIN) AF: 0.0534 AC: 566 AN: 10590

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0117 AC: 795 AN: 67958

Other (OTH) AF: 0.0617 AC: 130 AN: 2106

Alfa AF: 0.00898 Hom.: 1

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.62
PhyloP100		-2.0
PromoterAI		0.0029	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34819629; hg19: chr2-242794620;