dbSNP rs10183087: ICOS:c.*2A>C (chr2-203959601-A-C) – ACMG Classification: Benign (-20 pts)

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.*2A>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 0.258 in 1,608,482 control chromosomes in the GnomAD database, including 56,426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7110 hom., cov: 31)

Exomes 𝑓: 0.25 ( 49316 hom. )

Consequence

ICOS
NM_012092.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0390

Publications

27 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

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

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-203959601-A-C is Benign according to our data. Variant chr2-203959601-A-C is described in ClinVar as Benign. ClinVar VariationId is 333739.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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	NM_012092.4	MANE Select	c.*2A>C		3_prime_UTR	Exon 5 of 5	NP_036224.1	Q53QY6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ICOS	ENST00000316386.11	TSL:1 MANE Select	c.*2A>C	3_prime_UTR	Exon 5 of 5	ENSP00000319476.6	Q9Y6W8-1
ICOS	ENST00000435193.1	TSL:1	c.*10A>C	3_prime_UTR	Exon 4 of 4	ENSP00000415951.1	Q9Y6W8-2
ICOS	ENST00000897354.1		c.*2A>C	3_prime_UTR	Exon 4 of 4	ENSP00000567413.1

Frequencies

GnomAD3 genomes

AF:

0.292

AC:

44388

AN:

151824

Hom.:

7077

Cov.:

show subpopulations

Gnomad AFR

AF:

0.412

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.290

Gnomad ASJ

AF:

0.239

Gnomad EAS

AF:

0.199

Gnomad SAS

AF:

0.339

Gnomad FIN

AF:

0.226

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.287

GnomAD2 exomes

AF:

0.263

AC:

66074

AN:

251258

AF XY:

0.264

show subpopulations

Gnomad AFR exome

AF:

0.417

Gnomad AMR exome

AF:

0.264

Gnomad ASJ exome

AF:

0.248

Gnomad EAS exome

AF:

0.205

Gnomad FIN exome

AF:

0.224

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.247

GnomAD4 exome

AF:

0.255

AC:

370955

AN:

1456540

Hom.:

49316

Cov.:

AF XY:

0.257

AC XY:

186114

AN XY:

724904

show subpopulations

African (AFR)

AF:

0.424

AC:

14050

AN:

33158

American (AMR)

AF:

0.269

AC:

12037

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

6527

AN:

26104

East Asian (EAS)

AF:

0.190

AC:

7540

AN:

39666

South Asian (SAS)

AF:

0.339

AC:

29155

AN:

86126

European-Finnish (FIN)

AF:

0.222

AC:

11831

AN:

53398

Middle Eastern (MID)

AF:

0.294

AC:

1692

AN:

5762

European-Non Finnish (NFE)

AF:

0.246

AC:

272290

AN:

1107414

Other (OTH)

AF:

0.263

AC:

15833

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

12760

25519

38279

51038

63798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9470

18940

28410

37880

47350

<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:

0.293

AC:

44477

AN:

151942

Hom.:

7110

Cov.:

AF XY:

0.292

AC XY:

21722

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.412

AC:

17050

AN:

41366

American (AMR)

AF:

0.290

AC:

4437

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

827

AN:

3464

East Asian (EAS)

AF:

0.197

AC:

1017

AN:

5156

South Asian (SAS)

AF:

0.338

AC:

1625

AN:

4802

European-Finnish (FIN)

AF:

0.226

AC:

2390

AN:

10572

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16261

AN:

67996

Other (OTH)

AF:

0.293

AC:

617

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1551

3102

4652

6203

7754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.257

Hom.:

22071

Bravo

AF:

0.300

Asia WGS

AF:

0.310

AC:

1078

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency, common variable, 1 (2)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.4

(source)

DANN

Benign

0.74

PhyloP100

-0.039

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over