2-203956715-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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. 15/20 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 0.538

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 497910.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}. Variant chr2-203956715-G-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICOS	NM_012092.4	c.451G>C	p.Val151Leu	missense_variant	3/5	ENST00000316386.11
ICOS	XM_047444022.1	c.454G>C	p.Val152Leu	missense_variant	3/5
ICOS	XR_007073112.1	n.503G>C		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOS	ENST00000316386.11	c.451G>C	p.Val151Leu	missense_variant	3/5	1	NM_012092.4	P2
ICOS	ENST00000435193.1	c.451G>C	p.Val151Leu	missense_variant	3/4	1		A2

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152144 Hom.: 1 Cov.: 32

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

GnomAD3 exomes AF: 0.000876 AC: 220 AN: 251192 Hom.: 0 AF XY: 0.000715 AC XY: 97 AN XY: 135738

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 SAS exome AF: 0.0000653

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.: 1 Cov.: 30 AF XY: 0.000472 AC XY: 343 AN XY: 726950

Gnomad4 AFR exome AF: 0.00595

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000334

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00216 AC: 329 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74446

Gnomad4 AFR AF: 0.00613

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000716 Hom.: 0

Bravo AF: 0.00285

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency, common variable, 1 Uncertain:2 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jan 18, 2023	This variant has been reported in the literature in 2 individuals with a clinical suspicion of immunodeficiency (1 as a homozygote, segregating with disease in 1 affected relative and 1 as a heterozygote (Abolhassani 2019 PMID:29921932, Bisgin 2021 PMID:33859323). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.6% [256/41450] including 1 homozygote; https://gnomad.broadinstitute.org/variant/2-203956715-G-C?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Likely Benign (Variation ID: 497910). Evolutionary conservation and computational prediction tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 26, 2016

- -

ICOS-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

This variant is classified as likely 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	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	8.3
Dann	Benign	0.60
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.084
Sift	Benign	0.28	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.015	B;B
Vest4		0.33
MVP		0.14
MPC		0.36
ClinPred		0.0028	T
GERP RS		1.2
Varity_R		0.056
gMVP		0.41

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: rs76778263; hg19: chr2-204821438;