chr2-203951852-T-C

Variant names:

• chr2-203951852-T-C
• rs4521021
• NM_012092.4:c.59-3784T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012092.4(ICOS):​c.59-3784T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,072 control chromosomes in the GnomAD database, including 5,873 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5873 hom., cov: 32)
• Consequence: ICOS NM_012092.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.887
• Publications: 5 publications found

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: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• immunodeficiency, common variable, 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICOS	NM_012092.4	c.59-3784T>C		intron_variant	Intron 1 of 4	ENST00000316386.11	NP_036224.1
ICOS	XM_047444022.1	c.62-3784T>C		intron_variant	Intron 1 of 4		XP_047299978.1
ICOS	XR_007073112.1	n.111-3784T>C		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.59-3784T>C		intron_variant	Intron 1 of 4	1	NM_012092.4	ENSP00000319476.6
ICOS	ENST00000435193.1	c.59-3784T>C		intron_variant	Intron 1 of 3	1		ENSP00000415951.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38915 AN: 151954 Hom.: 5857 Cov.: 32

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0861

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.196

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.256 AC: 38991 AN: 152072 Hom.: 5873 Cov.: 32 AF XY: 0.252 AC XY: 18720 AN XY: 74332

African (AFR) AF: 0.388 AC: 16062 AN: 41442

American (AMR) AF: 0.179 AC: 2733 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 397 AN: 3472

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5188

South Asian (SAS) AF: 0.0866 AC: 418 AN: 4826

European-Finnish (FIN) AF: 0.337 AC: 3559 AN: 10566

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15166 AN: 67982

Other (OTH) AF: 0.194 AC: 408 AN: 2104

Alfa AF: 0.218 Hom.: 5946

Bravo AF: 0.252

Asia WGS AF: 0.0760 AC: 265 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.56
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4521021; hg19: chr2-204816575;