2-241851281-G-A

Position:

chr2-241851281-G-A

Variant summary

Our verdict is Benign. Variant got -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. 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

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.195

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
PDCD1	NM_005018.3 linkuse as main transcript	c.644C>T	p.Ala215Val	missense_variant	5/5	ENST00000334409.10	NP_005009.2	Q15116A0A0M3M0G7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PDCD1	ENST00000334409.10 linkuse as main transcript	c.644C>T	p.Ala215Val	missense_variant	5/5	1	NM_005018.3	ENSP00000335062.5	Q15116
PDCD1	ENST00000343705.3 linkuse as main transcript	c.317C>T	p.Ala106Val	missense_variant	3/3	1		ENSP00000340808.4	H0Y2W6
PDCD1	ENST00000418831.1 linkuse as main transcript	n.*207C>T		non_coding_transcript_exon_variant	5/5	1		ENSP00000390296.1	E7ER21
PDCD1	ENST00000418831.1 linkuse as main transcript	n.*207C>T		3_prime_UTR_variant	5/5	1		ENSP00000390296.1	E7ER21

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

GnomAD3 exomes

AF:

0.0922

AC:

22974

AN:

249124

Hom.:

3756

AF XY:

0.0823

AC XY:

11096

AN XY:

134770

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 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.:

AF XY:

0.0369

AC XY:

26751

AN XY:

724998

show subpopulations

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.:

AF XY:

0.0576

AC XY:

4288

AN XY:

74434

show subpopulations

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:

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 24269013, 30540488) -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Benign

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

MutationTaster

Benign

1.0

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over