Genetic Variant CD28:c.-198_-197insC (chr2-203706326-T-TC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The ENST00000458610.6(CD28):c.-198_-197insC variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 559,698 control chromosomes in the GnomAD database, including 56 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.013 ( 18 hom., cov: 31)

Exomes 𝑓: 0.010 ( 38 hom. )

Consequence

CD28
ENST00000458610.6 upstream_gene

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.235

Publications

2 publications found

Variant links:

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: LIMITED Submitted by: Ambry Genetics

CD28 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1990/151934) while in subpopulation AFR AF = 0.0191 (793/41440). AF 95% confidence interval is 0.018. There are 18 homozygotes in GnomAd4. There are 989 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD28	NM_001410981.1 link	c.-198_-197insC		upstream_gene_variant			NP_001397910.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	Protein
CD28	ENST00000458610.6 link	c.-198_-197insC	upstream_gene_variant	1	ENSP00000393648.2
CD28	ENST00000374481.8 link	c.-371_-370insC	upstream_gene_variant	1	ENSP00000363605.4
CD28	ENST00000718458.1 link	c.-198_-197insC	upstream_gene_variant		ENSP00000520836.1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1979

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0190

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.00635

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.0193

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00962

Gnomad OTH

AF:

0.0163

GnomAD4 exome

AF:

0.0103

AC:

4203

AN:

407764

Hom.:

AF XY:

0.0106

AC XY:

2260

AN XY:

212972

show subpopulations

African (AFR)

AF:

0.0213

AC:

250

AN:

11742

American (AMR)

AF:

0.0107

AC:

173

AN:

16126

Ashkenazi Jewish (ASJ)

AF:

0.00775

AC:

100

AN:

12904

East Asian (EAS)

AF:

0.000202

AC:

AN:

29768

South Asian (SAS)

AF:

0.0165

AC:

567

AN:

34380

European-Finnish (FIN)

AF:

0.0152

AC:

414

AN:

27276

Middle Eastern (MID)

AF:

0.0352

AC:

AN:

1818

European-Non Finnish (NFE)

AF:

0.00940

AC:

2344

AN:

249486

Other (OTH)

AF:

0.0117

AC:

285

AN:

24264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

205

411

616

822

1027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0131

AC:

1990

AN:

151934

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

989

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.0191

AC:

793

AN:

41440

American (AMR)

AF:

0.0116

AC:

176

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00635

AC:

AN:

3464

East Asian (EAS)

AF:

0.000388

AC:

AN:

5152

South Asian (SAS)

AF:

0.0135

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0193

AC:

204

AN:

10562

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00962

AC:

654

AN:

67970

Other (OTH)

AF:

0.0161

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

196

295

393

491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.0129

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.23

Splicing

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

Publications

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2-203706326-TC-TCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over