2-203706740-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD28	NM_006139.4	c.44A>G	p.Gln15Arg	missense_variant	Exon 1 of 4	ENST00000324106.9	NP_006130.1
CD28	NM_001243077.2	c.44A>G	p.Gln15Arg	missense_variant	Exon 1 of 4		NP_001230006.1
CD28	NM_001243078.2	c.44A>G	p.Gln15Arg	missense_variant	Exon 1 of 3		NP_001230007.1
CD28	NM_001410981.1	c.94+123A>G		intron_variant	Intron 1 of 3		NP_001397910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD28	ENST00000324106.9	c.44A>G	p.Gln15Arg	missense_variant	Exon 1 of 4	1	NM_006139.4	ENSP00000324890.7
CD28	ENST00000374481.7	c.44A>G	p.Gln15Arg	missense_variant	Exon 1 of 3	1		ENSP00000363605.4
CD28	ENST00000458610.6	c.94+123A>G		intron_variant	Intron 1 of 3	1		ENSP00000393648.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44A>G (p.Q15R) alteration is located in exon 1 (coding exon 1) of the CD28 gene. This alteration results from a A to G substitution at nucleotide position 44, causing the glutamine (Q) at amino acid position 15 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.053	T;D
Sift4G	Benign	0.071	T;T
Polyphen		0.095	B;P
Vest4		0.42
MutPred		0.41		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.88
MPC		0.21
ClinPred		0.84	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs199547990; hg19: chr2-204571463;