rs4521021

chr2-203951852-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	UniProt
ICOS	NM_012092.4	c.59-3784T>C		intron_variant		ENST00000316386.11
ICOS	XM_047444022.1	c.62-3784T>C		intron_variant
ICOS	XR_007073112.1	n.111-3784T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOS	ENST00000316386.11	c.59-3784T>C		intron_variant		1	NM_012092.4	P2
ICOS	ENST00000435193.1	c.59-3784T>C		intron_variant		1		A2

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

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.0866

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.194

Alfa AF: 0.214 Hom.: 3938

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

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: rs4521021; hg19: chr2-204816575;