2-203955633-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012092.4(ICOS):​c.59-3C>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 0.0000227 in 1,452,370 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ICOS
NM_012092.4 splice_region, intron

Scores

2
Splicing: ADA: 0.4810
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.40
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.2).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ICOSNM_012092.4 linkc.59-3C>T splice_region_variant, intron_variant Intron 1 of 4 ENST00000316386.11 NP_036224.1 Q9Y6W8-1Q53QY6
ICOSXM_047444022.1 linkc.62-3C>T splice_region_variant, intron_variant Intron 1 of 4 XP_047299978.1
ICOSXR_007073112.1 linkn.111-3C>T splice_region_variant, intron_variant Intron 1 of 5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ICOSENST00000316386.11 linkc.59-3C>T splice_region_variant, intron_variant Intron 1 of 4 1 NM_012092.4 ENSP00000319476.6 Q9Y6W8-1
ICOSENST00000435193.1 linkc.59-3C>T splice_region_variant, intron_variant Intron 1 of 3 1 ENSP00000415951.1 Q9Y6W8-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
249522
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135256
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000981
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000227
AC:
33
AN:
1452370
Hom.:
0
Cov.:
29
AF XY:
0.0000221
AC XY:
16
AN XY:
723246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000581
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000236
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 1 Uncertain:1
Jun 16, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 1 of the ICOS gene. It does not directly change the encoded amino acid sequence of the ICOS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs764098873, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ICOS-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1
Jan 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ICOS: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.20
CADD
Benign
14
DANN
Benign
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.48
dbscSNV1_RF
Benign
0.21
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: rs764098873; hg19: chr2-204820356; API