2-203729683-C-G

Variant names:

• chr2-203729683-C-G
• rs772079144
• NM_006139.4:c.445C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006139.4(CD28):​c.445C>G​(p.Pro149Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. P149S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CD28 NM_006139.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.204

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09055787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD28	NM_006139.4	c.445C>G	p.Pro149Ala	missense_variant	Exon 3 of 4	ENST00000324106.9	NP_006130.1
CD28	NM_001410981.1	c.487C>G	p.Pro163Ala	missense_variant	Exon 3 of 4		NP_001397910.1
CD28	NM_001243077.2	c.154C>G	p.Pro52Ala	missense_variant	Exon 3 of 4		NP_001230006.1
CD28	NM_001243078.2	c.88C>G	p.Pro30Ala	missense_variant	Exon 2 of 3		NP_001230007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD28	ENST00000324106.9	c.445C>G	p.Pro149Ala	missense_variant	Exon 3 of 4	1	NM_006139.4	ENSP00000324890.7
CD28	ENST00000458610.6	c.487C>G	p.Pro163Ala	missense_variant	Exon 3 of 4	1		ENSP00000393648.2
CD28	ENST00000374481.7	c.88C>G	p.Pro30Ala	missense_variant	Exon 2 of 3	1		ENSP00000363605.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251448 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461760 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	1.5
DANN	Benign	0.13
DEOGEN2	Uncertain	0.48	.;.;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.90	.;.;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.7	.;N;N
REVEL	Benign	0.10
Sift	Benign	0.13	.;T;T
Sift4G	Benign	0.099	T;T;T
Polyphen		0.40	B;.;B
Vest4		0.19
MutPred		0.27		.;.;Gain of catalytic residue at P149 (P = 0.0262);
MVP		0.71
MPC		0.19
ClinPred		0.11	T
GERP RS		0.68
Varity_R		0.030
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs772079144; hg19: chr2-204594406;