2-203956715-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_012092.4(ICOS):c.451G>C(p.Val151Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000684 in 1,613,512 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V151I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 1 hom. )

Consequence

ICOS
NM_012092.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 0.538

Publications

3 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: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
immunodeficiency, common variable, 1
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ICOS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047225356).

BP6

Variant 2-203956715-G-C is Benign according to our data. Variant chr2-203956715-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 497910.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00216 (329/152262) while in subpopulation AFR AF = 0.00613 (255/41572). AF 95% confidence interval is 0.00552. There are 1 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.451G>C	p.Val151Leu	missense	Exon 3 of 5	NP_036224.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ICOS	ENST00000316386.11	TSL:1 MANE Select	c.451G>C	p.Val151Leu	missense	Exon 3 of 5	ENSP00000319476.6
ICOS	ENST00000435193.1	TSL:1	c.451G>C	p.Val151Leu	missense	Exon 3 of 4	ENSP00000415951.1
ICOS	ENST00000897354.1		c.115G>C	p.Val39Leu	missense	Exon 2 of 4	ENSP00000567413.1

Frequencies

GnomAD3 genomes

AF:

0.00217

AC:

330

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00618

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000876

AC:

220

AN:

251192

AF XY:

0.000715

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000530

AC:

774

AN:

1461250

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

343

AN XY:

726950

show subpopulations

African (AFR)

AF:

0.00595

AC:

199

AN:

33448

American (AMR)

AF:

0.00123

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000334

AC:

371

AN:

1111516

Other (OTH)

AF:

0.00126

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00216

AC:

329

AN:

152262

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00613

AC:

255

AN:

41572

American (AMR)

AF:

0.00183

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000716

Hom.:

Bravo

AF:

0.00285

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000749

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000655

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency, common variable, 1 (5)

not provided (2)

ICOS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.3

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.17

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.59

M_CAP

Benign

0.0033

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.54

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

REVEL

Benign

0.084

Sift

Benign

0.28

Sift4G

Benign

0.33

Polyphen

0.015

Vest4

0.33

MVP

0.14

MPC

0.36

ClinPred

0.0028

GERP RS

1.2

Varity_R

0.056

gMVP

0.41

Mutation Taster

=35/65

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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