rs10183087

Positions:

• chr2-203959601-A-C
• chr2-203959601-A-G
• chr2-203959601-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000316386.11(ICOS):​c.*2A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,608,482 control chromosomes in the GnomAD database, including 56,426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7110 hom., cov: 31)
  • Exomes 𝑓: 0.25 (49316 hom.)
• Consequence: ICOS ENST00000316386.11 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0390

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-203959601-A-C is Benign according to our data. Variant chr2-203959601-A-C is described in ClinVar as [Benign]. Clinvar id is 333739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICOS	NM_012092.4	c.*2A>C		3_prime_UTR_variant	5/5	ENST00000316386.11	NP_036224.1
ICOS	XM_047444022.1	c.*2A>C		3_prime_UTR_variant	5/5		XP_047299978.1
ICOS	XR_007073112.1	n.767A>C		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.*2A>C		3_prime_UTR_variant	5/5	1	NM_012092.4	ENSP00000319476	P2
ICOS	ENST00000435193.1	c.*10A>C		3_prime_UTR_variant	4/4	1		ENSP00000415951	A2

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44388 AN: 151824 Hom.: 7077 Cov.: 31

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.287

GnomAD3 exomes AF: 0.263 AC: 66074 AN: 251258 Hom.: 9239 AF XY: 0.264 AC XY: 35865 AN XY: 135818

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.264

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.205

Gnomad SAS exome AF: 0.344

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.255 AC: 370955 AN: 1456540 Hom.: 49316 Cov.: 32 AF XY: 0.257 AC XY: 186114 AN XY: 724904

Gnomad4 AFR exome AF: 0.424

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.222

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.293 AC: 44477 AN: 151942 Hom.: 7110 Cov.: 31 AF XY: 0.292 AC XY: 21722 AN XY: 74264

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.197

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.293

Alfa AF: 0.253 Hom.: 10084

Bravo AF: 0.300

Asia WGS AF: 0.310 AC: 1078 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 56. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.74

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: rs10183087; hg19: chr2-204824324; COSMIC: COSV57029517;