2-203936854-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (13 hom.)
• Consequence: ICOS NM_012092.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.89

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]

LOC101927840 (HGNC:):

ACMG classification

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 GnomAd at 15 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOS	ENST00000316386.11	c.40C>T	p.Arg14Cys	missense_variant	1/5	1	NM_012092.4	P2
ICOS	ENST00000435193.1	c.40C>T	p.Arg14Cys	missense_variant	1/4	1		A2

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1113 AN: 151982 Hom.: 15 Cov.: 32

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.: 4 AF XY: 0.00148 AC XY: 201 AN XY: 135712

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.: 13 Cov.: 29 AF XY: 0.000620 AC XY: 450 AN XY: 725690

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.: 15 Cov.: 32 AF XY: 0.00683 AC XY: 508 AN XY: 74340

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.: 3

Bravo AF: 0.00824

ESP6500AA AF: 0.0266 AC: 117

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00241 AC: 292

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

ICOS-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Uncertain	25
Dann	Benign	0.87
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.061
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.88	D;D
PrimateAI	Benign	0.28	T
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	T
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

Other links and lift over

dbSNP: rs77411896; hg19: chr2-204801577;