NM_001252.5:c.345C>T

Variant names:

• chr19-6586257-G-A
• rs1862511
• NM_001252.5:c.345C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001252.5(CD70):​c.345C>T​(p.Cys115Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,613,640 control chromosomes in the GnomAD database, including 77,706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6608 hom., cov: 31)
  • Exomes 𝑓: 0.30 (71098 hom.)
• Consequence: CD70 NM_001252.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21
• Publications: 16 publications found

Genes affected

CD70 (HGNC:11937): (CD70 molecule) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for TNFRSF27/CD27. It is a surface antigen on activated, but not on resting, T and B lymphocytes. It induces proliferation of costimulated T cells, enhances the generation of cytolytic T cells, and contributes to T cell activation. This cytokine is also reported to play a role in regulating B-cell activation, cytotoxic function of natural killer cells, and immunoglobulin sythesis. [provided by RefSeq, Jul 2008]

CD70 Gene-Disease associations (from GenCC):

• severe combined immunodeficiency due to CD70 deficiency

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 19-6586257-G-A is Benign according to our data. Variant chr19-6586257-G-A is described in ClinVar as Benign. ClinVar VariationId is 2628186.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001252.5. 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
	CD70	NM_001252.5	MANE Select	c.345C>T	p.Cys115Cys	synonymous	Exon 3 of 3	NP_001243.1
	CD70	NM_001330332.2		c.345C>T	p.Cys115Cys	synonymous	Exon 3 of 4	NP_001317261.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD70	ENST00000245903.4	TSL:1 MANE Select	c.345C>T	p.Cys115Cys	synonymous	Exon 3 of 3	ENSP00000245903.2
	CD70	ENST00000423145.7	TSL:2	c.345C>T	p.Cys115Cys	synonymous	Exon 3 of 4	ENSP00000395294.2

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42669 AN: 151908 Hom.: 6611 Cov.: 31

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.294

GnomAD2 exomes AF: 0.319 AC: 80052 AN: 251254 AF XY: 0.323

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.695

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.302 AC: 441946 AN: 1461614 Hom.: 71098 Cov.: 38 AF XY: 0.304 AC XY: 220865 AN XY: 727126

African (AFR) AF: 0.192 AC: 6421 AN: 33470

American (AMR) AF: 0.219 AC: 9798 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6552 AN: 26134

East Asian (EAS) AF: 0.686 AC: 27239 AN: 39698

South Asian (SAS) AF: 0.340 AC: 29329 AN: 86248

European-Finnish (FIN) AF: 0.380 AC: 20286 AN: 53386

Middle Eastern (MID) AF: 0.270 AC: 1530 AN: 5664

European-Non Finnish (NFE) AF: 0.290 AC: 322137 AN: 1111918

Other (OTH) AF: 0.309 AC: 18654 AN: 60378

GnomAD4 genome AF: 0.281 AC: 42672 AN: 152026 Hom.: 6608 Cov.: 31 AF XY: 0.288 AC XY: 21377 AN XY: 74292

African (AFR) AF: 0.199 AC: 8235 AN: 41478

American (AMR) AF: 0.251 AC: 3842 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 874 AN: 3470

East Asian (EAS) AF: 0.685 AC: 3517 AN: 5134

South Asian (SAS) AF: 0.356 AC: 1720 AN: 4828

European-Finnish (FIN) AF: 0.388 AC: 4103 AN: 10572

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19374 AN: 67952

Other (OTH) AF: 0.296 AC: 625 AN: 2108

Alfa AF: 0.287 Hom.: 27187

Bravo AF: 0.272

Asia WGS AF: 0.477 AC: 1656 AN: 3478

EpiCase AF: 0.293

EpiControl AF: 0.298

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

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 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 46. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.0
DANN	Benign	0.65
PhyloP100		1.2
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: rs1862511; hg19: chr19-6586268; COSMIC: COSV55566324; COSMIC: COSV55566324;