rs2227982

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 976 hom., cov: 32)

Exomes 𝑓: 0.037 ( 6973 hom. )

Consequence

PDCD1
NM_005018.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.195

Publications

109 publications found

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 Gene-Disease associations (from GenCC):

systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

PDCD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

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.644C>T	p.Ala215Val	missense	Exon 5 of 5	NP_005009.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PDCD1	ENST00000334409.10	TSL:1 MANE Select	c.644C>T	p.Ala215Val	missense	Exon 5 of 5	ENSP00000335062.5
PDCD1	ENST00000343705.4	TSL:1	c.488C>T	p.Ala163Val	missense	Exon 4 of 4	ENSP00000340808.4
PDCD1	ENST00000418831.1	TSL:1	n.*207C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000390296.1

Frequencies

GnomAD3 genomes

AF:

0.0493

AC:

7505

AN:

152136

Hom.:

967

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0922

AC:

22974

AN:

249124

AF XY:

0.0823

show subpopulations

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 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.:

AF XY:

0.0369

AC XY:

26751

AN XY:

724998

show subpopulations

African (AFR)

AF:

0.0101

AC:

338

AN:

33374

American (AMR)

AF:

0.259

AC:

11504

AN:

44466

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

351

AN:

25946

East Asian (EAS)

AF:

0.481

AC:

19083

AN:

39652

South Asian (SAS)

AF:

0.0625

AC:

5375

AN:

86060

European-Finnish (FIN)

AF:

0.0502

AC:

2665

AN:

53100

Middle Eastern (MID)

AF:

0.00681

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0113

AC:

12579

AN:

1109688

Other (OTH)

AF:

0.0440

AC:

2649

AN:

60184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2144

4289

6433

8578

10722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

862

1724

2586

3448

4310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0494

AC:

7528

AN:

152254

Hom.:

976

Cov.:

AF XY:

0.0576

AC XY:

4288

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0123

AC:

512

AN:

41566

American (AMR)

AF:

0.174

AC:

2664

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3470

East Asian (EAS)

AF:

0.474

AC:

2448

AN:

5164

South Asian (SAS)

AF:

0.0766

AC:

369

AN:

4818

European-Finnish (FIN)

AF:

0.0530

AC:

562

AN:

10598

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0117

AC:

798

AN:

68030

Other (OTH)

AF:

0.0636

AC:

134

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

292

583

875

1166

1458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0335

Hom.:

1964

Bravo

AF:

0.0595

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.0803

AC:

9752

Asia WGS

AF:

0.242

AC:

840

AN:

3478

EpiCase

AF:

0.00905

EpiControl

AF:

0.00949

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.56

MetaRNN

Benign

0.00043

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.6

PhyloP100

-0.20

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.2

REVEL

Benign

0.16

Sift

Uncertain

0.019

Sift4G

Benign

0.24

Polyphen

0.82

Vest4

0.017

MPC

0.39

ClinPred

0.0045

GERP RS

2.9

Varity_R

0.045

gMVP

0.30

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over