2-203937855-T-C

Variant names:

• chr2-203937855-T-C
• rs4675374
• NM_012092.4:c.58+983T>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.58+983T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 152,126 control chromosomes in the GnomAD database, including 35,264 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 0.66 (35264 hom., cov: 32)
• Consequence: ICOS NM_012092.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.128
• Publications: 45 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)

ENSG00000300710 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICOS	NM_012092.4	c.58+983T>C		intron_variant	Intron 1 of 4	ENST00000316386.11	NP_036224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.58+983T>C		intron_variant	Intron 1 of 4	1	NM_012092.4	ENSP00000319476.6
ICOS	ENST00000435193.1	c.58+983T>C		intron_variant	Intron 1 of 3	1		ENSP00000415951.1
ENSG00000300710	ENST00000773540.1	n.112-467A>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99658 AN: 152008 Hom.: 35263 Cov.: 32

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.807

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.669

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

GnomAD4 genome AF: 0.655 AC: 99669 AN: 152126 Hom.: 35264 Cov.: 32 AF XY: 0.658 AC XY: 48934 AN XY: 74354

African (AFR) AF: 0.366 AC: 15191 AN: 41488

American (AMR) AF: 0.741 AC: 11325 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2303 AN: 3468

East Asian (EAS) AF: 0.598 AC: 3089 AN: 5166

South Asian (SAS) AF: 0.787 AC: 3789 AN: 4816

European-Finnish (FIN) AF: 0.807 AC: 8549 AN: 10592

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 53174 AN: 67988

Other (OTH) AF: 0.672 AC: 1419 AN: 2112

Alfa AF: 0.738 Hom.: 147573

Bravo AF: 0.634

Asia WGS AF: 0.716 AC: 2490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.9
DANN	Benign	0.71
PhyloP100		-0.13
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: rs4675374; hg19: chr2-204802578;