2-203959560-T-G

Variant names:

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.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

Publications

12 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)

ICOS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012092.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	NM_012092.4	MANE Select	c.587-26T>G		intron	N/A	NP_036224.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	ENST00000316386.11	TSL:1 MANE Select	c.587-26T>G		intron	N/A	ENSP00000319476.6
	ICOS	ENST00000435193.1	TSL:1	c.502-26T>G		intron	N/A	ENSP00000415951.1

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

GnomAD2 exomes

AF:

0.572

AC:

143554

AN:

250814

AF XY:

0.573

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 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

African (AFR)

AF:

0.517

AC:

17062

AN:

33002

American (AMR)

AF:

0.537

AC:

24000

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.598

AC:

15574

AN:

26058

East Asian (EAS)

AF:

0.492

AC:

19493

AN:

39622

South Asian (SAS)

AF:

0.509

AC:

43784

AN:

85940

European-Finnish (FIN)

AF:

0.602

AC:

32139

AN:

53370

Middle Eastern (MID)

AF:

0.585

AC:

3356

AN:

5738

European-Non Finnish (NFE)

AF:

0.627

AC:

690590

AN:

1100702

Other (OTH)

AF:

0.590

AC:

35375

AN:

59928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

15786

31572

47358

63144

78930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18198

36396

54594

72792

90990

<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

AF:

0.574

AC:

87127

AN:

151800

Hom.:

25305

Cov.:

AF XY:

0.568

AC XY:

42085

AN XY:

74140

show subpopulations

African (AFR)

AF:

0.516

AC:

21335

AN:

41352

American (AMR)

AF:

0.554

AC:

8453

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.581

AC:

2015

AN:

3468

East Asian (EAS)

AF:

0.451

AC:

2325

AN:

5150

South Asian (SAS)

AF:

0.492

AC:

2364

AN:

4800

European-Finnish (FIN)

AF:

0.603

AC:

6341

AN:

10520

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.625

AC:

42447

AN:

67938

Other (OTH)

AF:

0.584

AC:

1228

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1837

3675

5512

7350

9187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

734

1468

2202

2936

3670

<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:

0.603

Hom.:

36887

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

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.

Immunodeficiency, common variable, 1

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.0

(source)

DANN

Benign

0.49

PhyloP100

-0.0060

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over