19-6586387-C-G

Variant names:

• chr19-6586387-C-G
• rs774636584
• NM_001252.5:c.215G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001252.5(CD70):​c.215G>C​(p.Arg72Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,610,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R72K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CD70 NM_001252.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.676
• Publications: 0 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: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18364605).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD70	NM_001252.5	MANE Select	c.215G>C	p.Arg72Thr	missense	Exon 3 of 3	NP_001243.1	P32970-1
	CD70	NM_001330332.2		c.215G>C	p.Arg72Thr	missense	Exon 3 of 4	NP_001317261.1	P32970-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD70	ENST00000245903.4	TSL:1 MANE Select	c.215G>C	p.Arg72Thr	missense	Exon 3 of 3	ENSP00000245903.2	P32970-1
	CD70	ENST00000423145.7	TSL:2	c.215G>C	p.Arg72Thr	missense	Exon 3 of 4	ENSP00000395294.2	P32970-2
	CD70	ENST00000894984.1		c.215G>C	p.Arg72Thr	missense	Exon 4 of 4	ENSP00000565043.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458046 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725116

African (AFR) AF: 0.0000299 AC: 1 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110574

Other (OTH) AF: 0.00 AC: 0 AN: 60176

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152274 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74458

African (AFR) AF: 0.0000722 AC: 3 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.089	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.68
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.093
Sift	Benign	0.25	T
Sift4G	Benign	0.43	T
Polyphen		0.056	B
Vest4		0.31
MutPred		0.25		Gain of phosphorylation at R72 (P = 0.0728)
MVP		0.93
MPC		1.3
ClinPred		0.12	T
GERP RS		0.43
Varity_R		0.074
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs774636584; hg19: chr19-6586398;