rs4264550

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_012092.4(ICOS):c.501+6C>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,555,586 control chromosomes in the GnomAD database, including 1 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 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 1 hom. )

Consequence

ICOS
NM_012092.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.00005473

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

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]

ICOS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-203956771-C-G is Benign according to our data. Variant chr2-203956771-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 624172.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr2-203956771-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000309 (47/151954) while in subpopulation NFE AF= 0.000632 (43/67986). AF 95% confidence interval is 0.000482. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
ICOS	NM_012092.4 linkuse as main transcript	c.501+6C>G	splice_donor_region_variant, intron_variant	ENST00000316386.11
ICOS	XM_047444022.1 linkuse as main transcript	c.504+6C>G	splice_donor_region_variant, intron_variant
ICOS	XR_007073112.1 linkuse as main transcript	n.553+6C>G	splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOS	ENST00000316386.11 linkuse as main transcript	c.501+6C>G		splice_donor_region_variant, intron_variant		1	NM_012092.4	P2	Q9Y6W8-1
ICOS	ENST00000435193.1 linkuse as main transcript	c.501+6C>G		splice_donor_region_variant, intron_variant		1		A2	Q9Y6W8-2

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000267

AC:

AN:

250604

Hom.:

AF XY:

0.000273

AC XY:

AN XY:

135426

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000503

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000680

AC:

955

AN:

1403632

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

452

AN XY:

701924

show subpopulations

Gnomad4 AFR exome

AF:

0.000186

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.000880

Gnomad4 OTH exome

AF:

0.000171

GnomAD4 genome

AF:

0.000309

AC:

AN:

151954

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.0000967

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000239

Hom.:

360

EpiCase

AF:

0.000600

EpiControl

AF:

0.000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2022

This sequence change falls in intron 3 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 (rs4264550, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ICOS-related conditions. ClinVar contains an entry for this variant (Variation ID: 624172). 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

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2018

- -

ICOS-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.7

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.028

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over