2-203959560-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012092.4(ICOS):c.587-26T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 1,600,854 control chromosomes in the GnomAD database, including 295,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.57 ( 25305 hom., cov: 30)

Exomes 𝑓: 0.61 ( 270647 hom. )

Consequence

ICOS
NM_012092.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.00600

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 -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 2-203959560-T-G is Benign according to our data. Variant chr2-203959560-T-G is described in ClinVar as [Benign]. Clinvar id is 1285249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ICOS	NM_012092.4 link	c.587-26T>G	intron_variant	Intron 4 of 4	ENST00000316386.11	NP_036224.1	Q9Y6W8-1Q53QY6
ICOS	XM_047444022.1 link	c.590-26T>G	intron_variant	Intron 4 of 4		XP_047299978.1
ICOS	XR_007073112.1 link	n.752-26T>G	intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11 link	c.587-26T>G		intron_variant	Intron 4 of 4	1	NM_012092.4	ENSP00000319476.6		Q9Y6W8-1
ICOS	ENST00000435193.1 link	c.502-26T>G		intron_variant	Intron 3 of 3	1		ENSP00000415951.1		Q9Y6W8-2

Frequencies

GnomAD3 genomes

AF:

0.574

AC:

87025

AN:

151682

Hom.:

25264

Cov.:

show subpopulations

Gnomad AFR

AF:

0.515

Gnomad AMI

AF:

0.499

Gnomad AMR

AF:

0.553

Gnomad ASJ

AF:

0.581

Gnomad EAS

AF:

0.452

Gnomad SAS

AF:

0.493

Gnomad FIN

AF:

0.603

Gnomad MID

AF:

0.563

Gnomad NFE

AF:

0.625

Gnomad OTH

AF:

0.580

GnomAD3 exomes

AF:

0.572

AC:

143554

AN:

250814

Hom.:

41561

AF XY:

0.573

AC XY:

77674

AN XY:

135636

show subpopulations

Gnomad AFR exome

AF:

0.519

Gnomad AMR exome

AF:

0.527

Gnomad ASJ exome

AF:

0.593

Gnomad EAS exome

AF:

0.448

Gnomad SAS exome

AF:

0.508

Gnomad FIN exome

AF:

0.598

Gnomad NFE exome

AF:

0.624

Gnomad OTH exome

AF:

0.590

GnomAD4 exome

AF:

0.608

AC:

881373

AN:

1449054

Hom.:

270647

Cov.:

AF XY:

0.606

AC XY:

437012

AN XY:

721586

show subpopulations

Gnomad4 AFR exome

AF:

0.517

Gnomad4 AMR exome

AF:

0.537

Gnomad4 ASJ exome

AF:

0.598

Gnomad4 EAS exome

AF:

0.492

Gnomad4 SAS exome

AF:

0.509

Gnomad4 FIN exome

AF:

0.602

Gnomad4 NFE exome

AF:

0.627

Gnomad4 OTH exome

AF:

0.590

GnomAD4 genome

AF:

0.574

AC:

87127

AN:

151800

Hom.:

25305

Cov.:

AF XY:

0.568

AC XY:

42085

AN XY:

74140

show subpopulations

Gnomad4 AFR

AF:

0.516

Gnomad4 AMR

AF:

0.554

Gnomad4 ASJ

AF:

0.581

Gnomad4 EAS

AF:

0.451

Gnomad4 SAS

AF:

0.492

Gnomad4 FIN

AF:

0.603

Gnomad4 NFE

AF:

0.625

Gnomad4 OTH

AF:

0.584

Alfa

AF:

0.607

Hom.:

29060

Bravo

AF:

0.569

Asia WGS

AF:

0.483

AC:

1681

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Immunodeficiency, common variable, 1

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 81% of patients studied by a panel of primary immunodeficiencies. Number of patients: 77. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.0

DANN

Benign

0.49

BranchPoint Hunter

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

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.

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