rs199547990

Variant names:

• chr2-203706740-A-G
• rs199547990
• NM_006139.4:c.44A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006139.4(CD28):​c.44A>G​(p.Gln15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,457,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CD28 NM_006139.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67
• Publications: 0 publications found

Genes affected

CD28 (HGNC:1653): (CD28 molecule) The protein encoded by this gene is essential for T-cell proliferation and survival, cytokine production, and T-helper type-2 development. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

CD28 Gene-Disease associations (from GenCC):

• immunodeficiency 123 with HPV-related verrucosis

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35332346).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006139.4. 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
	CD28	NM_006139.4	MANE Select	c.44A>G	p.Gln15Arg	missense	Exon 1 of 4	NP_006130.1	P10747-1
	CD28	NM_001243077.2		c.44A>G	p.Gln15Arg	missense	Exon 1 of 4	NP_001230006.1	P10747-4
	CD28	NM_001243078.2		c.44A>G	p.Gln15Arg	missense	Exon 1 of 3	NP_001230007.1	P10747-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD28	ENST00000324106.9	TSL:1 MANE Select	c.44A>G	p.Gln15Arg	missense	Exon 1 of 4	ENSP00000324890.7	P10747-1
	CD28	ENST00000374481.8	TSL:1	c.44A>G	p.Gln15Arg	missense	Exon 1 of 3	ENSP00000363605.4	P10747-2
	CD28	ENST00000458610.6	TSL:1	c.94+123A>G		intron	N/A	ENSP00000393648.2	P10747-7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000892 AC: 13 AN: 1457590 Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9 AN XY: 725402

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1108144

Other (OTH) AF: 0.00 AC: 0 AN: 60240

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.056
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.38
Sift	Benign	0.053	T
Sift4G	Benign	0.071	T
Polyphen		0.095	B
Vest4		0.42
MutPred		0.41		Loss of sheet (P = 0.0084)
MVP		0.88
MPC		0.21
ClinPred		0.84	D
GERP RS		5.7
PromoterAI		0.057	Neutral
Varity_R		0.23
gMVP		0.64
Mutation Taster		=80/20	polymorphism

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: rs199547990; hg19: chr2-204571463;