2-241851121-A-G

Variant names:

• chr2-241851121-A-G
• rs2227981
• NM_005018.3:c.804T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005018.3(PDCD1):​c.804T>C​(p.Ala268Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,612,824 control chromosomes in the GnomAD database, including 293,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A268A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.61 (28401 hom., cov: 33)
  • Exomes 𝑓: 0.60 (264751 hom.)
• Consequence: PDCD1 NM_005018.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.22

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 2-241851121-A-G is Benign according to our data. Variant chr2-241851121-A-G is described in ClinVar as [Benign]. Clinvar id is 1226460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD1	NM_005018.3	c.804T>C	p.Ala268Ala	synonymous_variant	Exon 5 of 5	ENST00000334409.10	NP_005009.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDCD1	ENST00000334409.10	c.804T>C	p.Ala268Ala	synonymous_variant	Exon 5 of 5	1	NM_005018.3	ENSP00000335062.5
PDCD1	ENST00000418831.1	n.*367T>C		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000390296.1
PDCD1	ENST00000418831.1	n.*367T>C		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000390296.1
PDCD1	ENST00000343705.3	c.*112T>C		downstream_gene_variant		1		ENSP00000340808.4

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92431 AN: 152000 Hom.: 28361 Cov.: 33

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.639

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.650

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.602

GnomAD3 exomes AF: 0.632 AC: 157353 AN: 249102 Hom.: 50287 AF XY: 0.636 AC XY: 85918 AN XY: 135056

Gnomad AFR exome AF: 0.579

Gnomad AMR exome AF: 0.621

Gnomad ASJ exome AF: 0.618

Gnomad EAS exome AF: 0.728

Gnomad SAS exome AF: 0.750

Gnomad FIN exome AF: 0.709

Gnomad NFE exome AF: 0.582

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.600 AC: 875807 AN: 1460706 Hom.: 264751 Cov.: 51 AF XY: 0.604 AC XY: 438894 AN XY: 726674

Gnomad4 AFR exome AF: 0.580

Gnomad4 AMR exome AF: 0.625

Gnomad4 ASJ exome AF: 0.622

Gnomad4 EAS exome AF: 0.701

Gnomad4 SAS exome AF: 0.744

Gnomad4 FIN exome AF: 0.703

Gnomad4 NFE exome AF: 0.578

Gnomad4 OTH exome AF: 0.610

GnomAD4 genome AF: 0.608 AC: 92526 AN: 152118 Hom.: 28401 Cov.: 33 AF XY: 0.620 AC XY: 46094 AN XY: 74368

Gnomad4 AFR AF: 0.577

Gnomad4 AMR AF: 0.640

Gnomad4 ASJ AF: 0.617

Gnomad4 EAS AF: 0.725

Gnomad4 SAS AF: 0.755

Gnomad4 FIN AF: 0.715

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.606

Alfa AF: 0.566 Hom.: 8552

Bravo AF: 0.597

Asia WGS AF: 0.737 AC: 2562 AN: 3478

EpiCase AF: 0.586

EpiControl AF: 0.583

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 87% of patients studied by a panel of primary immunodeficiencies. Number of patients: 83. Only high quality variants are reported. -

PDCD1-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.090
DANN	Benign	0.29

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: rs2227981; hg19: chr2-242793273; COSMIC: COSV57691079; COSMIC: COSV57691079;