2-203951659-A-G

Variant names:

• chr2-203951659-A-G
• rs4355090
• NM_012092.4:c.59-3977A>G

Variant summary

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

The NM_012092.4(ICOS):​c.59-3977A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 152,064 control chromosomes in the GnomAD database, including 8,012 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 0.32 (8012 hom., cov: 32)
• Consequence: ICOS NM_012092.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICOS	NM_012092.4	c.59-3977A>G		intron_variant	Intron 1 of 4	ENST00000316386.11	NP_036224.1
ICOS	XM_047444022.1	c.62-3977A>G		intron_variant	Intron 1 of 4		XP_047299978.1
ICOS	XR_007073112.1	n.111-3977A>G		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.59-3977A>G		intron_variant	Intron 1 of 4	1	NM_012092.4	ENSP00000319476.6
ICOS	ENST00000435193.1	c.59-3977A>G		intron_variant	Intron 1 of 3	1		ENSP00000415951.1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48179 AN: 151946 Hom.: 7997 Cov.: 32

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.365

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

GnomAD4 genome AF: 0.317 AC: 48237 AN: 152064 Hom.: 8012 Cov.: 32 AF XY: 0.315 AC XY: 23416 AN XY: 74334

African (AFR) AF: 0.343 AC: 14221 AN: 41460

American (AMR) AF: 0.359 AC: 5487 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1442 AN: 3472

East Asian (EAS) AF: 0.482 AC: 2488 AN: 5166

South Asian (SAS) AF: 0.240 AC: 1156 AN: 4812

European-Finnish (FIN) AF: 0.210 AC: 2218 AN: 10584

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19907 AN: 67982

Other (OTH) AF: 0.364 AC: 768 AN: 2112

Alfa AF: 0.304 Hom.: 9110

Bravo AF: 0.331

Asia WGS AF: 0.378 AC: 1315 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	0.29
DANN	Benign	0.55
PhyloP100		-1.6
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

Publications

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Other links and lift over

dbSNP: rs4355090; hg19: chr2-204816382;