chr2-203956771-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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	Effect	Exon rank	MANE	Protein	UniProt
ICOS	NM_012092.4 link	c.501+6C>T	splice_region_variant, intron_variant	Intron 3 of 4	ENST00000316386.11	NP_036224.1	Q9Y6W8-1Q53QY6
ICOS	XM_047444022.1 link	c.504+6C>T	splice_region_variant, intron_variant	Intron 3 of 4		XP_047299978.1
ICOS	XR_007073112.1 link	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 link	c.501+6C>T		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_012092.4	ENSP00000319476.6		Q9Y6W8-1
ICOS	ENST00000435193.1 link	c.501+6C>T		splice_region_variant, intron_variant	Intron 3 of 3	1		ENSP00000415951.1		Q9Y6W8-2

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20769

AN:

151918

Hom.:

1506

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.157

AC:

39363

AN:

250604

Hom.:

3462

AF XY:

0.163

AC XY:

22082

AN XY:

135426

show subpopulations

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 SAS exome

AF:

0.261

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.:

AF XY:

0.159

AC XY:

111277

AN XY:

701004

show subpopulations

Gnomad4 AFR exome

AF:

0.103

Gnomad4 AMR exome

AF:

0.164

Gnomad4 ASJ exome

AF:

0.196

Gnomad4 EAS exome

AF:

0.154

Gnomad4 SAS exome

AF:

0.255

Gnomad4 FIN exome

AF:

0.106

Gnomad4 NFE exome

AF:

0.149

Gnomad4 OTH exome

AF:

0.165

GnomAD4 genome

AF:

0.137

AC:

20783

AN:

152036

Hom.:

1512

Cov.:

AF XY:

0.139

AC XY:

10362

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.103

Gnomad4 AMR

AF:

0.168

Gnomad4 ASJ

AF:

0.185

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.259

Gnomad4 FIN

AF:

0.113

Gnomad4 NFE

AF:

0.141

Gnomad4 OTH

AF:

0.152

Alfa

AF:

0.110

Hom.:

360

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

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 1

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 specified

Benign:2

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 -

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. -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

5.0

DANN

Benign

0.37

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over