2-203956891-C-G

Variant names:

• chr2-203956891-C-G
• rs4270326
• NM_012092.4:c.501+126C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012092.4(ICOS):​c.501+126C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 696,374 control chromosomes in the GnomAD database, including 10,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (1930 hom., cov: 32)
  • Exomes 𝑓: 0.16 (8177 hom.)
• Consequence: ICOS NM_012092.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.48
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-203956891-C-G is Benign according to our data. Variant chr2-203956891-C-G is described in ClinVar as Benign. ClinVar VariationId is 1296788.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.27 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	NM_012092.4	MANE Select	c.501+126C>G		intron	N/A	NP_036224.1	Q53QY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOS	ENST00000316386.11	TSL:1 MANE Select	c.501+126C>G		intron	N/A	ENSP00000319476.6	Q9Y6W8-1
	ICOS	ENST00000435193.1	TSL:1	c.501+126C>G		intron	N/A	ENSP00000415951.1	Q9Y6W8-2
	ICOS	ENST00000897354.1		c.165+126C>G		intron	N/A	ENSP00000567413.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23618 AN: 151978 Hom.: 1922 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.171

GnomAD4 exome AF: 0.164 AC: 89504 AN: 544278 Hom.: 8177 AF XY: 0.172 AC XY: 50162 AN XY: 292138

African (AFR) AF: 0.163 AC: 2483 AN: 15240

American (AMR) AF: 0.174 AC: 5753 AN: 33038

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 3939 AN: 18982

East Asian (EAS) AF: 0.158 AC: 4938 AN: 31306

South Asian (SAS) AF: 0.278 AC: 16828 AN: 60454

European-Finnish (FIN) AF: 0.105 AC: 4261 AN: 40692

Middle Eastern (MID) AF: 0.227 AC: 540 AN: 2384

European-Non Finnish (NFE) AF: 0.146 AC: 45811 AN: 312766

Other (OTH) AF: 0.168 AC: 4951 AN: 29416

GnomAD4 genome AF: 0.155 AC: 23638 AN: 152096 Hom.: 1930 Cov.: 32 AF XY: 0.158 AC XY: 11733 AN XY: 74344

African (AFR) AF: 0.163 AC: 6742 AN: 41470

American (AMR) AF: 0.177 AC: 2701 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 688 AN: 3472

East Asian (EAS) AF: 0.152 AC: 787 AN: 5174

South Asian (SAS) AF: 0.282 AC: 1359 AN: 4818

European-Finnish (FIN) AF: 0.112 AC: 1186 AN: 10594

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9638 AN: 67980

Other (OTH) AF: 0.169 AC: 356 AN: 2108

Alfa AF: 0.136 Hom.: 156

Bravo AF: 0.156

Asia WGS AF: 0.223 AC: 776 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.33
DANN	Benign	0.81
PhyloP100		-1.5
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: rs4270326; hg19: chr2-204821614;