2-241852039-G-C

Position:

• chr2-241852039-G-C

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.593-56C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.049 in 1,569,616 control chromosomes in the GnomAD database, including 2,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (125 hom., cov: 28)
  • Exomes 𝑓: 0.050 (1988 hom.)
• Consequence: PDCD1 NM_005018.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.309

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 (BayesDel_noAF=-0.95).
• BP6: Variant 2-241852039-G-C is Benign according to our data. Variant chr2-241852039-G-C is described in ClinVar as [Benign]. Clinvar id is 1260387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDCD1	NM_005018.3	c.593-56C>G		intron_variant		ENST00000334409.10	NP_005009.2
PDCD1	XM_006712573.3	c.*34C>G		3_prime_UTR_variant	4/4		XP_006712636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDCD1	ENST00000334409.10	c.593-56C>G		intron_variant		1	NM_005018.3	ENSP00000335062.5
PDCD1	ENST00000343705.3	c.266-56C>G		intron_variant		1		ENSP00000340808.4
PDCD1	ENST00000418831.1	n.*156-56C>G		intron_variant		1		ENSP00000390296.1

Frequencies

GnomAD3 genomes AF: 0.0387 AC: 5421 AN: 140132 Hom.: 124 Cov.: 28

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.000968

Gnomad SAS AF: 0.0502

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0540

Gnomad OTH AF: 0.0347

GnomAD4 exome AF: 0.0500 AC: 71524 AN: 1429422 Hom.: 1988 Cov.: 28 AF XY: 0.0508 AC XY: 36062 AN XY: 710336

Gnomad4 AFR exome AF: 0.00828

Gnomad4 AMR exome AF: 0.0167

Gnomad4 ASJ exome AF: 0.0394

Gnomad4 EAS exome AF: 0.000229

Gnomad4 SAS exome AF: 0.0564

Gnomad4 FIN exome AF: 0.0574

Gnomad4 NFE exome AF: 0.0541

Gnomad4 OTH exome AF: 0.0445

GnomAD4 genome AF: 0.0387 AC: 5424 AN: 140194 Hom.: 125 Cov.: 28 AF XY: 0.0377 AC XY: 2590 AN XY: 68708

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.000970

Gnomad4 SAS AF: 0.0509

Gnomad4 FIN AF: 0.0576

Gnomad4 NFE AF: 0.0540

Gnomad4 OTH AF: 0.0343

Alfa AF: 0.0266 Hom.: 17

Bravo AF: 0.0312

Asia WGS AF: 0.0180 AC: 64 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.58
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs55829775; hg19: chr2-242794191;