NM_005018.3:c.804T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 138 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
• autoimmune disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD1	NM_005018.3	MANE Select	c.804T>C	p.Ala268Ala	synonymous	Exon 5 of 5	NP_005009.2	Q15116

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD1	ENST00000334409.10	TSL:1 MANE Select	c.804T>C	p.Ala268Ala	synonymous	Exon 5 of 5	ENSP00000335062.5	Q15116
	PDCD1	ENST00000343705.4	TSL:1	c.648T>C	p.Ala216Ala	synonymous	Exon 4 of 4	ENSP00000340808.4	H0Y2W6
	PDCD1	ENST00000418831.1	TSL:1	n.*367T>C		non_coding_transcript_exon	Exon 5 of 5	ENSP00000390296.1	E7ER21

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

GnomAD2 exomes AF: 0.632 AC: 157353 AN: 249102 AF XY: 0.636

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 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

African (AFR) AF: 0.580 AC: 19412 AN: 33480

American (AMR) AF: 0.625 AC: 27908 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 16255 AN: 26124

East Asian (EAS) AF: 0.701 AC: 27836 AN: 39694

South Asian (SAS) AF: 0.744 AC: 64199 AN: 86244

European-Finnish (FIN) AF: 0.703 AC: 36955 AN: 52570

Middle Eastern (MID) AF: 0.632 AC: 3637 AN: 5758

European-Non Finnish (NFE) AF: 0.578 AC: 642795 AN: 1111790

Other (OTH) AF: 0.610 AC: 36810 AN: 60364

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

African (AFR) AF: 0.577 AC: 23937 AN: 41506

American (AMR) AF: 0.640 AC: 9788 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2139 AN: 3468

East Asian (EAS) AF: 0.725 AC: 3743 AN: 5160

South Asian (SAS) AF: 0.755 AC: 3639 AN: 4820

European-Finnish (FIN) AF: 0.715 AC: 7578 AN: 10604

Middle Eastern (MID) AF: 0.644 AC: 188 AN: 292

European-Non Finnish (NFE) AF: 0.582 AC: 39576 AN: 67944

Other (OTH) AF: 0.606 AC: 1282 AN: 2114

Alfa AF: 0.572 Hom.: 12197

Bravo AF: 0.597

Asia WGS AF: 0.737 AC: 2562 AN: 3478

EpiCase AF: 0.586

EpiControl AF: 0.583

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	PDCD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.090
DANN	Benign	0.29
PhyloP100		-3.2
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: rs2227981; hg19: chr2-242793273; COSMIC: COSV57691079; COSMIC: COSV57691079;