2-203956771-C-T

Variant names:

• chr2-203956771-C-T
• rs4264550
• NM_012092.4:c.501+6C>T

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.501+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,553,720 control chromosomes in the GnomAD database, including 19,510 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1512 hom., cov: 32)
  • Exomes 𝑓: 0.16 (17998 hom.)
• Consequence: ICOS NM_012092.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001369
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.636
• Publications: 10 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=-0.87).
• BP6: Variant 2-203956771-C-T is Benign according to our data. Variant chr2-203956771-C-T is described in ClinVar as Benign. ClinVar VariationId is 333735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICOS	NM_012092.4	c.501+6C>T		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000316386.11	NP_036224.1
ICOS	XM_047444022.1	c.504+6C>T		splice_region_variant, intron_variant	Intron 3 of 4		XP_047299978.1
ICOS	XR_007073112.1	n.553+6C>T		splice_region_variant, intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.501+6C>T		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_012092.4	ENSP00000319476.6
ICOS	ENST00000435193.1	c.501+6C>T		splice_region_variant, intron_variant	Intron 3 of 3	1		ENSP00000415951.1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20769 AN: 151918 Hom.: 1506 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.157 AC: 39363 AN: 250604 AF XY: 0.163

Gnomad AFR exome AF: 0.0987

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.156 AC: 217971 AN: 1401684 Hom.: 17998 Cov.: 24 AF XY: 0.159 AC XY: 111277 AN XY: 701004

African (AFR) AF: 0.103 AC: 3319 AN: 32260

American (AMR) AF: 0.164 AC: 7328 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 5052 AN: 25728

East Asian (EAS) AF: 0.154 AC: 6058 AN: 39332

South Asian (SAS) AF: 0.255 AC: 21700 AN: 85094

European-Finnish (FIN) AF: 0.106 AC: 5643 AN: 53328

Middle Eastern (MID) AF: 0.226 AC: 1271 AN: 5622

European-Non Finnish (NFE) AF: 0.149 AC: 157991 AN: 1057348

Other (OTH) AF: 0.165 AC: 9609 AN: 58398

GnomAD4 genome AF: 0.137 AC: 20783 AN: 152036 Hom.: 1512 Cov.: 32 AF XY: 0.139 AC XY: 10362 AN XY: 74322

African (AFR) AF: 0.103 AC: 4263 AN: 41464

American (AMR) AF: 0.168 AC: 2561 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 641 AN: 3470

East Asian (EAS) AF: 0.152 AC: 784 AN: 5172

South Asian (SAS) AF: 0.259 AC: 1245 AN: 4808

European-Finnish (FIN) AF: 0.113 AC: 1191 AN: 10580

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.141 AC: 9596 AN: 67962

Other (OTH) AF: 0.152 AC: 322 AN: 2112

Alfa AF: 0.121 Hom.: 590

Bravo AF: 0.135

Asia WGS AF: 0.211 AC: 734 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.156

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 1 Benign:3

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 40% of patients studied by a panel of primary immunodeficiencies. Number of patients: 38. 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 -

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	-0.87
CADD	Benign	5.0
DANN	Benign	0.37
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs4264550; hg19: chr2-204821494; COSMIC: COSV57029989;