2-203936854-C-T

Position:

chr2-203936854-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012092.4(ICOS):c.40C>T(p.Arg14Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,610,374 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 13 hom. )

Consequence

ICOS
NM_012092.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.89

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:

LOC101927840 (HGNC:):

LOC101927840 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035465658).

BP6

Variant 2-203936854-C-T is Benign according to our data. Variant chr2-203936854-C-T is described in ClinVar as [Benign]. Clinvar id is 439812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00732 (1114/152102) while in subpopulation AFR AF= 0.0257 (1066/41474). AF 95% confidence interval is 0.0244. There are 15 homozygotes in gnomad4. There are 508 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ICOS	NM_012092.4 linkuse as main transcript	c.40C>T	p.Arg14Cys	missense_variant	1/5	ENST00000316386.11	NP_036224.1
LOC101927840	XR_427213.4 linkuse as main transcript	n.314+463G>A		intron_variant, non_coding_transcript_variant
ICOS	XR_007073112.1 linkuse as main transcript	n.92C>T		non_coding_transcript_exon_variant	1/6
ICOS	XM_047444022.1 linkuse as main transcript			upstream_gene_variant			XP_047299978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11 linkuse as main transcript	c.40C>T	p.Arg14Cys	missense_variant	1/5	1	NM_012092.4	ENSP00000319476	P2	Q9Y6W8-1
ICOS	ENST00000435193.1 linkuse as main transcript	c.40C>T	p.Arg14Cys	missense_variant	1/4	1		ENSP00000415951	A2	Q9Y6W8-2

Frequencies

GnomAD3 genomes

AF:

0.00732

AC:

1113

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0257

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00194

AC:

488

AN:

250972

Hom.:

AF XY:

0.00148

AC XY:

201

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.0275

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000726

AC:

1059

AN:

1458272

Hom.:

Cov.:

AF XY:

0.000620

AC XY:

450

AN XY:

725690

show subpopulations

Gnomad4 AFR exome

AF:

0.0270

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.00109

GnomAD4 genome

AF:

0.00732

AC:

1114

AN:

152102

Hom.:

Cov.:

AF XY:

0.00683

AC XY:

508

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0257

Gnomad4 AMR

AF:

0.00210

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.000956

Hom.:

Bravo

AF:

0.00824

ESP6500AA

AF:

0.0266

AC:

117

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00241

AC:

292

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Immunodeficiency, common variable, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

- -

ICOS-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2023

This variant is classified as 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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

DANN

Benign

0.87

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-0.061

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

0.88

D;D

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.019

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

0.39

B;P

Vest4

0.22

MVP

0.45

MPC

0.47

ClinPred

0.024

GERP RS

5.6

Varity_R

0.11

gMVP

0.85

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

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