2-203729743-C-A

Position:

• chr2-203729743-C-A

Variant summary

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

The NM_006139.4(CD28):​c.505C>A​(p.Leu169Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: CD28 NM_006139.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.510

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=0.26105183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD28	NM_006139.4	c.505C>A	p.Leu169Ile	missense_variant	3/4	ENST00000324106.9	NP_006130.1
CD28	NM_001410981.1	c.547C>A	p.Leu183Ile	missense_variant	3/4		NP_001397910.1
CD28	NM_001243077.2	c.214C>A	p.Leu72Ile	missense_variant	3/4		NP_001230006.1
CD28	NM_001243078.2	c.148C>A	p.Leu50Ile	missense_variant	2/3		NP_001230007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD28	ENST00000324106.9	c.505C>A	p.Leu169Ile	missense_variant	3/4	1	NM_006139.4	ENSP00000324890	P1
CD28	ENST00000458610.6	c.547C>A	p.Leu183Ile	missense_variant	3/4	1		ENSP00000393648
CD28	ENST00000374481.7	c.148C>A	p.Leu50Ile	missense_variant	2/3	1		ENSP00000363605

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The c.505C>A (p.L169I) alteration is located in exon 3 (coding exon 3) of the CD28 gene. This alteration results from a C to A substitution at nucleotide position 505, causing the leucine (L) at amino acid position 169 to be replaced by an isoleucine (I). 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	0.094
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	.;.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.7	.;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	.;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.027	.;D;D
Sift4G	Benign	0.076	T;T;T
Polyphen		0.96	D;.;P
Vest4		0.30
MutPred		0.28		.;.;Loss of helix (P = 0.079);
MVP		0.80
MPC		0.38
ClinPred		0.63	D
GERP RS		0.36
Varity_R		0.097
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-204594466;