2-203729683-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006139.4(CD28):​c.445C>T​(p.Pro149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CD28 NM_006139.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03993222).
• BP6: Variant 2-203729683-C-T is Benign according to our data. Variant chr2-203729683-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2530704.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD28	NM_006139.4	c.445C>T	p.Pro149Ser	missense_variant	Exon 3 of 4	ENST00000324106.9	NP_006130.1
CD28	NM_001410981.1	c.487C>T	p.Pro163Ser	missense_variant	Exon 3 of 4		NP_001397910.1
CD28	NM_001243077.2	c.154C>T	p.Pro52Ser	missense_variant	Exon 3 of 4		NP_001230006.1
CD28	NM_001243078.2	c.88C>T	p.Pro30Ser	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>T	p.Pro149Ser	missense_variant	Exon 3 of 4	1	NM_006139.4	ENSP00000324890.7
CD28	ENST00000458610.6	c.487C>T	p.Pro163Ser	missense_variant	Exon 3 of 4	1		ENSP00000393648.2
CD28	ENST00000374481.7	c.88C>T	p.Pro30Ser	missense_variant	Exon 2 of 3	1		ENSP00000363605.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251448 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 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: 0.0000224

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

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.25
DANN	Benign	0.13
DEOGEN2	Benign	0.37	.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.39	.;.;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.96	.;N;N
REVEL	Benign	0.14
Sift	Benign	1.0	.;T;T
Sift4G	Benign	0.86	T;T;T
Polyphen		0.018	B;.;B
Vest4		0.14
MutPred		0.27		.;.;Gain of disorder (P = 0.1189);
MVP		0.54
MPC		0.20
ClinPred		0.055	T
GERP RS		0.68
Varity_R		0.024
gMVP		0.40

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: rs772079144; hg19: chr2-204594406;