2-241851760-C-T

Variant names:

• chr2-241851760-C-T
• rs11568821
• NM_005018.3:c.627+189G>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.627+189G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0758 in 152,192 control chromosomes in the GnomAD database, including 593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.076 (593 hom., cov: 32)
• Consequence: PDCD1 NM_005018.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.19
• Publications: 115 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=-0.98).
• BP6: Variant 2-241851760-C-T is Benign according to our data. Variant chr2-241851760-C-T is described in ClinVar as Benign. ClinVar VariationId is 1265148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 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.627+189G>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.627+189G>A		intron	N/A	ENSP00000335062.5
	PDCD1	ENST00000343705.4	TSL:1	c.471+189G>A		intron	N/A	ENSP00000340808.4
	PDCD1	ENST00000418831.1	TSL:1	n.*190+189G>A		intron	N/A	ENSP00000390296.1

Frequencies

GnomAD3 genomes AF: 0.0759 AC: 11538 AN: 152074 Hom.: 593 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0839

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0967

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0758 AC: 11536 AN: 152192 Hom.: 593 Cov.: 32 AF XY: 0.0728 AC XY: 5416 AN XY: 74406

African (AFR) AF: 0.0202 AC: 840 AN: 41532

American (AMR) AF: 0.0838 AC: 1281 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 497 AN: 3470

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5166

South Asian (SAS) AF: 0.0417 AC: 201 AN: 4822

European-Finnish (FIN) AF: 0.0585 AC: 620 AN: 10604

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7739 AN: 67988

Other (OTH) AF: 0.0957 AC: 202 AN: 2110

Alfa AF: 0.0691 Hom.: 222

Bravo AF: 0.0758

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12402038, 18401354, 17999073, 15912506)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.13
DANN	Benign	0.67
PhyloP100		-4.2
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: rs11568821; hg19: chr2-242793912;