2-203937257-T-C

Variant names:

• chr2-203937257-T-C
• rs4335928
• NM_012092.4:c.58+385T>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+385T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0855 in 152,214 control chromosomes in the GnomAD database, including 717 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 0.086 (717 hom., cov: 32)
• Consequence: ICOS NM_012092.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.106
• Publications: 9 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012092.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	NM_012092.4	MANE Select	c.58+385T>C		intron	N/A	NP_036224.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	ENST00000316386.11	TSL:1 MANE Select	c.58+385T>C		intron	N/A	ENSP00000319476.6
	ICOS	ENST00000435193.1	TSL:1	c.58+385T>C		intron	N/A	ENSP00000415951.1
	ICOS	ENST00000897354.1		c.58+385T>C		intron	N/A	ENSP00000567413.1

Frequencies

GnomAD3 genomes AF: 0.0856 AC: 13019 AN: 152096 Hom.: 716 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.0866

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0686

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0975

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

GnomAD4 genome AF: 0.0855 AC: 13019 AN: 152214 Hom.: 717 Cov.: 32 AF XY: 0.0854 AC XY: 6353 AN XY: 74412

African (AFR) AF: 0.0206 AC: 855 AN: 41546

American (AMR) AF: 0.0866 AC: 1324 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3472

East Asian (EAS) AF: 0.123 AC: 634 AN: 5170

South Asian (SAS) AF: 0.0693 AC: 334 AN: 4820

European-Finnish (FIN) AF: 0.115 AC: 1214 AN: 10598

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7915 AN: 68000

Other (OTH) AF: 0.0984 AC: 208 AN: 2114

Alfa AF: 0.108 Hom.: 1224

Bravo AF: 0.0822

Asia WGS AF: 0.0910 AC: 315 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		0.11
PromoterAI		-0.0040	Neutral
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: rs4335928; hg19: chr2-204801980;