chr2-203956771-C-T

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

2
Splicing: ADA: 0.00001369
2

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]

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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 HGVSp Effect Exon rank MANE Protein UniProt
ICOSNM_012092.4 linkc.501+6C>T splice_region_variant, intron_variant Intron 3 of 4 ENST00000316386.11 NP_036224.1 Q9Y6W8-1Q53QY6
ICOSXM_047444022.1 linkc.504+6C>T splice_region_variant, intron_variant Intron 3 of 4 XP_047299978.1
ICOSXR_007073112.1 linkn.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
ICOSENST00000316386.11 linkc.501+6C>T splice_region_variant, intron_variant Intron 3 of 4 1 NM_012092.4 ENSP00000319476.6 Q9Y6W8-1
ICOSENST00000435193.1 linkc.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.:
32
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.:
24
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.:
32
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.

Other links and lift over

dbSNP: rs4264550; hg19: chr2-204821494; COSMIC: COSV57029989; API