chr2-203959601-A-C

Variant names:

• chr2-203959601-A-C
• rs10183087
• NM_012092.4:c.*2A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012092.4(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 NM_012092.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0390
• Publications: 27 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 -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 VariationId 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 rank	MANE	Protein	UniProt
ICOS	NM_012092.4	c.*2A>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000316386.11	NP_036224.1
ICOS	XR_007073112.1	n.767A>C		non_coding_transcript_exon_variant	Exon 6 of 6
ICOS	XM_047444022.1	c.*2A>C		3_prime_UTR_variant	Exon 5 of 5		XP_047299978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.*2A>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_012092.4	ENSP00000319476.6
ICOS	ENST00000435193.1	c.*10A>C		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000415951.1

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

GnomAD2 exomes AF: 0.263 AC: 66074 AN: 251258 AF XY: 0.264

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 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

African (AFR) AF: 0.424 AC: 14050 AN: 33158

American (AMR) AF: 0.269 AC: 12037 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 6527 AN: 26104

East Asian (EAS) AF: 0.190 AC: 7540 AN: 39666

South Asian (SAS) AF: 0.339 AC: 29155 AN: 86126

European-Finnish (FIN) AF: 0.222 AC: 11831 AN: 53398

Middle Eastern (MID) AF: 0.294 AC: 1692 AN: 5762

European-Non Finnish (NFE) AF: 0.246 AC: 272290 AN: 1107414

Other (OTH) AF: 0.263 AC: 15833 AN: 60200

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

African (AFR) AF: 0.412 AC: 17050 AN: 41366

American (AMR) AF: 0.290 AC: 4437 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 827 AN: 3464

East Asian (EAS) AF: 0.197 AC: 1017 AN: 5156

South Asian (SAS) AF: 0.338 AC: 1625 AN: 4802

European-Finnish (FIN) AF: 0.226 AC: 2390 AN: 10572

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16261 AN: 67996

Other (OTH) AF: 0.293 AC: 617 AN: 2106

Alfa AF: 0.257 Hom.: 22071

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

not specified Benign:2

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Immunodeficiency, common variable, 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.74
PhyloP100		-0.039
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: rs10183087; hg19: chr2-204824324; COSMIC: COSV57029517;