rs140049646
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_012092.4(ICOS):c.58+9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,562,618 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0033 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00036 ( 4 hom. )
Consequence
ICOS
NM_012092.4 intron
NM_012092.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0300
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 -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
Variant 2-203936881-T-G is Benign according to our data. Variant chr2-203936881-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 333732.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr2-203936881-T-G is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0033 (503/152266) while in subpopulation AFR AF= 0.0112 (465/41550). AF 95% confidence interval is 0.0104. There are 3 homozygotes in gnomad4. There are 217 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ICOS | NM_012092.4 | c.58+9T>G | intron_variant | ENST00000316386.11 | |||
LOC101927840 | XR_427213.4 | n.314+436A>C | intron_variant, non_coding_transcript_variant | ||||
ICOS | XR_007073112.1 | n.110+9T>G | intron_variant, non_coding_transcript_variant | ||||
ICOS | XM_047444022.1 | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ICOS | ENST00000316386.11 | c.58+9T>G | intron_variant | 1 | NM_012092.4 | P2 | |||
ICOS | ENST00000435193.1 | c.58+9T>G | intron_variant | 1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00329 AC: 501AN: 152148Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.000932 AC: 233AN: 250090Hom.: 4 AF XY: 0.000621 AC XY: 84AN XY: 135340
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GnomAD4 exome AF: 0.000360 AC: 508AN: 1410352Hom.: 4 Cov.: 24 AF XY: 0.000321 AC XY: 226AN XY: 704980
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Immunodeficiency, common variable, 1 Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 02, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at