chr2-203960563-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012092.4(ICOS):​c.*964T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 152,192 control chromosomes in the GnomAD database, including 7,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7116 hom., cov: 32)
Failed GnomAD Quality Control

Consequence

ICOS
NM_012092.4 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.316

Publications

35 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: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
Variant 2-203960563-T-C is Benign according to our data. Variant chr2-203960563-T-C is described in ClinVar as Benign. ClinVar VariationId is 333747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ICOSNM_012092.4 linkc.*964T>C 3_prime_UTR_variant Exon 5 of 5 ENST00000316386.11 NP_036224.1 Q9Y6W8-1Q53QY6
ICOSXR_007073112.1 linkn.1729T>C non_coding_transcript_exon_variant Exon 6 of 6
ICOSXM_047444022.1 linkc.*964T>C 3_prime_UTR_variant Exon 5 of 5 XP_047299978.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ICOSENST00000316386.11 linkc.*964T>C 3_prime_UTR_variant Exon 5 of 5 1 NM_012092.4 ENSP00000319476.6 Q9Y6W8-1
ICOSENST00000435193.1 linkc.*972T>C 3_prime_UTR_variant Exon 4 of 4 1 ENSP00000415951.1 Q9Y6W8-2

Frequencies

GnomAD3 genomes
AF:
0.292
AC:
44419
AN:
152074
Hom.:
7082
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.411
Gnomad AMI
AF:
0.188
Gnomad AMR
AF:
0.289
Gnomad ASJ
AF:
0.238
Gnomad EAS
AF:
0.199
Gnomad SAS
AF:
0.344
Gnomad FIN
AF:
0.227
Gnomad MID
AF:
0.275
Gnomad NFE
AF:
0.238
Gnomad OTH
AF:
0.287
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AC:
0
AN:
0
Hom.:
0
Cov.:
0
AC XY:
0
AN XY:
0
African (AFR)
AC:
0
AN:
0
American (AMR)
AC:
0
AN:
0
Ashkenazi Jewish (ASJ)
AC:
0
AN:
0
East Asian (EAS)
AC:
0
AN:
0
South Asian (SAS)
AC:
0
AN:
0
European-Finnish (FIN)
AC:
0
AN:
0
Middle Eastern (MID)
AC:
0
AN:
0
European-Non Finnish (NFE)
AC:
0
AN:
0
Other (OTH)
AC:
0
AN:
0
GnomAD4 genome
AF:
0.292
AC:
44509
AN:
152192
Hom.:
7116
Cov.:
32
AF XY:
0.292
AC XY:
21729
AN XY:
74410
show subpopulations
African (AFR)
AF:
0.412
AC:
17085
AN:
41494
American (AMR)
AF:
0.290
AC:
4427
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.238
AC:
827
AN:
3472
East Asian (EAS)
AF:
0.197
AC:
1024
AN:
5186
South Asian (SAS)
AF:
0.344
AC:
1659
AN:
4826
European-Finnish (FIN)
AF:
0.227
AC:
2403
AN:
10596
Middle Eastern (MID)
AF:
0.279
AC:
82
AN:
294
European-Non Finnish (NFE)
AF:
0.238
AC:
16214
AN:
68020
Other (OTH)
AF:
0.292
AC:
617
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
1567
3133
4700
6266
7833
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
452
904
1356
1808
2260
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.260
Hom.:
7333
Bravo
AF:
0.299
Asia WGS
AF:
0.309
AC:
1077
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Feb 18, 2020
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25497975) -

Immunodeficiency, common variable, 1 Benign:1
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.91
CADD
Benign
6.1
DANN
Benign
0.55
PhyloP100
0.32
Mutation Taster
=100/0
polymorphism (auto)

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: rs4404254; hg19: chr2-204825286; API