rs2227982

chr2-241851281-G-A

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.644C>T(p.Ala215Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,610,454 control chromosomes in the GnomAD database, including 7,949 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.049 (976 hom., cov: 32)
  • Exomes 𝑓: 0.037 (6973 hom.)
• Consequence: PDCD1 NM_005018.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.195

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 (MetaRNN=4.2915344E-4).
• BP6: Variant 2-241851281-G-A is Benign according to our data. Variant chr2-241851281-G-A is described in ClinVar as [Benign]. Clinvar id is 1282693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDCD1	NM_005018.3	c.644C>T	p.Ala215Val	missense_variant	5/5	ENST00000334409.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDCD1	ENST00000334409.10	c.644C>T	p.Ala215Val	missense_variant	5/5	1	NM_005018.3	P1
PDCD1	ENST00000343705.3	c.320C>T	p.Ala107Val	missense_variant	3/3	1
PDCD1	ENST00000418831.1	c.*207C>T		3_prime_UTR_variant, NMD_transcript_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7505 AN: 152136 Hom.: 967 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.0763

Gnomad FIN AF: 0.0530

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0594

GnomAD3 exomes AF: 0.0922 AC: 22974 AN: 249124 Hom.: 3756 AF XY: 0.0823 AC XY: 11096 AN XY: 134770

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.487

Gnomad SAS exome AF: 0.0620

Gnomad FIN exome AF: 0.0519

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0610

GnomAD4 exome AF: 0.0374 AC: 54583 AN: 1458200 Hom.: 6973 Cov.: 35 AF XY: 0.0369 AC XY: 26751 AN XY: 724998

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.481

Gnomad4 SAS exome AF: 0.0625

Gnomad4 FIN exome AF: 0.0502

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.0440

GnomAD4 genome AF: 0.0494 AC: 7528 AN: 152254 Hom.: 976 Cov.: 32 AF XY: 0.0576 AC XY: 4288 AN XY: 74434

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.474

Gnomad4 SAS AF: 0.0766

Gnomad4 FIN AF: 0.0530

Gnomad4 NFE AF: 0.0117

Gnomad4 OTH AF: 0.0636

Alfa AF: 0.0329 Hom.: 862

Bravo AF: 0.0595

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.0803 AC: 9752

Asia WGS AF: 0.242 AC: 840 AN: 3478

EpiCase AF: 0.00905

EpiControl AF: 0.00949

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 37% of patients studied by a panel of primary immunodeficiencies. Number of patients: 35. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 24269013, 30540488) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	10
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.00043	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.16
Sift	Uncertain	0.019	D
Sift4G	Benign	0.24	T
Polyphen		0.82	P
Vest4		0.017
MPC		0.39
ClinPred		0.0045	T
GERP RS		2.9
Varity_R		0.045
gMVP		0.30

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

Other links and lift over

dbSNP: rs2227982; hg19: chr2-242793433; COSMIC: COSV57690833;