2-203955648-G-T

Position:

chr2-203955648-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012092.4(ICOS):c.71G>T(p.Gly24Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,611,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ICOS
NM_012092.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0450

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07130182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ICOS	NM_012092.4 linkuse as main transcript	c.71G>T	p.Gly24Val	missense_variant	2/5	ENST00000316386.11
ICOS	XM_047444022.1 linkuse as main transcript	c.74G>T	p.Gly25Val	missense_variant	2/5
ICOS	XR_007073112.1 linkuse as main transcript	n.123G>T		non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOS	ENST00000316386.11 linkuse as main transcript	c.71G>T	p.Gly24Val	missense_variant	2/5	1	NM_012092.4	P2	Q9Y6W8-1
ICOS	ENST00000435193.1 linkuse as main transcript	c.71G>T	p.Gly24Val	missense_variant	2/4	1		A2	Q9Y6W8-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250200

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135418

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1459568

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726274

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 24 of the ICOS protein (p.Gly24Val). This variant is present in population databases (rs774325808, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ICOS-related conditions. ClinVar contains an entry for this variant (Variation ID: 949085). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2022

The c.71G>T (p.G24V) alteration is located in exon 2 (coding exon 2) of the ICOS gene. This alteration results from a G to T substitution at nucleotide position 71, causing the glycine (G) at amino acid position 24 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.071

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

L;L

MutationTaster

Benign

0.65

D;D

PrimateAI

Benign

0.27

PROVEAN

Benign

1.0

N;N

REVEL

Benign

0.076

Sift

Benign

0.24

T;T

Sift4G

Uncertain

0.017

D;D

Polyphen

0.95

P;P

Vest4

0.13

MutPred

0.34

Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);

MVP

0.17

MPC

0.44

ClinPred

0.22

GERP RS

-0.17

Varity_R

0.15

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