chr2-203941729-A-G

Variant names:

• chr2-203941729-A-G
• rs7602383
• NM_012092.4:c.58+4857A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012092.4(ICOS):​c.58+4857A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 152,220 control chromosomes in the GnomAD database, including 1,526 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1526 hom., cov: 33)
• Consequence: ICOS NM_012092.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• Publications: 5 publications found

Genes affected

ICOS (HGNC:5351): (inducible T cell costimulator) The protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms homodimers and plays an important role in cell-cell signaling, immune responses, and regulation of cell proliferation. [provided by RefSeq, Jul 2008]

ICOS Gene-Disease associations (from GenCC):

• common variable immunodeficiency

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• immunodeficiency, common variable, 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012092.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	NM_012092.4	MANE Select	c.58+4857A>G		intron	N/A	NP_036224.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	ENST00000316386.11	TSL:1 MANE Select	c.58+4857A>G		intron	N/A	ENSP00000319476.6
	ICOS	ENST00000435193.1	TSL:1	c.58+4857A>G		intron	N/A	ENSP00000415951.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21234 AN: 152102 Hom.: 1524 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0830

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.142

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.140 AC: 21244 AN: 152220 Hom.: 1526 Cov.: 33 AF XY: 0.136 AC XY: 10140 AN XY: 74440

African (AFR) AF: 0.152 AC: 6302 AN: 41518

American (AMR) AF: 0.114 AC: 1748 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 557 AN: 3470

East Asian (EAS) AF: 0.120 AC: 624 AN: 5184

South Asian (SAS) AF: 0.0835 AC: 403 AN: 4828

European-Finnish (FIN) AF: 0.125 AC: 1328 AN: 10606

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9797 AN: 67998

Other (OTH) AF: 0.142 AC: 301 AN: 2114

Alfa AF: 0.142 Hom.: 395

Bravo AF: 0.141

Asia WGS AF: 0.105 AC: 367 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.4
DANN	Benign	0.69
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7602383; hg19: chr2-204806452;