chr2-203936854-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012092.4(ICOS):​c.40C>A​(p.Arg14Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,458,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14C) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ICOS
NM_012092.4 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.89

Publications

3 publications found
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 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13389078).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ICOSNM_012092.4 linkc.40C>A p.Arg14Ser missense_variant Exon 1 of 5 ENST00000316386.11 NP_036224.1 Q9Y6W8-1Q53QY6
ICOSXR_007073112.1 linkn.92C>A non_coding_transcript_exon_variant Exon 1 of 6
LOC101927840XR_427213.4 linkn.314+463G>T intron_variant Intron 2 of 3
ICOSXM_047444022.1 linkc.-3581C>A upstream_gene_variant XP_047299978.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ICOSENST00000316386.11 linkc.40C>A p.Arg14Ser missense_variant Exon 1 of 5 1 NM_012092.4 ENSP00000319476.6 Q9Y6W8-1
ICOSENST00000435193.1 linkc.40C>A p.Arg14Ser missense_variant Exon 1 of 4 1 ENSP00000415951.1 Q9Y6W8-2
ENSG00000300710ENST00000773540.1 linkn.183+463G>T intron_variant Intron 2 of 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1458282
Hom.:
0
Cov.:
29
AF XY:
0.00000551
AC XY:
4
AN XY:
725694
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33404
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26106
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39672
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86194
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52846
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1109264
Other (OTH)
AF:
0.00
AC:
0
AN:
60314
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
9
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
23
DANN
Benign
0.84
DEOGEN2
Benign
0.16
T;.
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.083
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.35
T;T
M_CAP
Benign
0.0035
T
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.34
N;N
PhyloP100
3.9
PrimateAI
Benign
0.28
T
PROVEAN
Benign
0.14
N;N
REVEL
Benign
0.11
Sift
Benign
0.13
T;T
Sift4G
Benign
0.13
T;T
Polyphen
0.0
B;B
Vest4
0.27
MutPred
0.40
Loss of MoRF binding (P = 0.0444);Loss of MoRF binding (P = 0.0444);
MVP
0.27
MPC
0.38
ClinPred
0.39
T
GERP RS
5.6
PromoterAI
0.011
Neutral
Varity_R
0.14
gMVP
0.76
Mutation Taster
=94/6
polymorphism

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

Publications

Other links and lift over

dbSNP: rs77411896; hg19: chr2-204801577; API