chr2-203956771-C-T

Variant names:

• chr2-203956771-C-T
• rs4264550
• NM_012092.4:c.501+6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012092.4(ICOS):​c.501+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,553,720 control chromosomes in the GnomAD database, including 19,510 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1512 hom., cov: 32)
  • Exomes 𝑓: 0.16 (17998 hom.)
• Consequence: ICOS NM_012092.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001369
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.636
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-203956771-C-T is Benign according to our data. Variant chr2-203956771-C-T is described in ClinVar as Benign. ClinVar VariationId is 333735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.247 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+6C>T		splice_region 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+6C>T		splice_region intron	N/A	ENSP00000319476.6	Q9Y6W8-1
	ICOS	ENST00000435193.1	TSL:1	c.501+6C>T		splice_region intron	N/A	ENSP00000415951.1	Q9Y6W8-2
	ICOS	ENST00000897354.1		c.165+6C>T		splice_region intron	N/A	ENSP00000567413.1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20769 AN: 151918 Hom.: 1506 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.157 AC: 39363 AN: 250604 AF XY: 0.163

Gnomad AFR exome AF: 0.0987

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.156 AC: 217971 AN: 1401684 Hom.: 17998 Cov.: 24 AF XY: 0.159 AC XY: 111277 AN XY: 701004

African (AFR) AF: 0.103 AC: 3319 AN: 32260

American (AMR) AF: 0.164 AC: 7328 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 5052 AN: 25728

East Asian (EAS) AF: 0.154 AC: 6058 AN: 39332

South Asian (SAS) AF: 0.255 AC: 21700 AN: 85094

European-Finnish (FIN) AF: 0.106 AC: 5643 AN: 53328

Middle Eastern (MID) AF: 0.226 AC: 1271 AN: 5622

European-Non Finnish (NFE) AF: 0.149 AC: 157991 AN: 1057348

Other (OTH) AF: 0.165 AC: 9609 AN: 58398

GnomAD4 genome AF: 0.137 AC: 20783 AN: 152036 Hom.: 1512 Cov.: 32 AF XY: 0.139 AC XY: 10362 AN XY: 74322

African (AFR) AF: 0.103 AC: 4263 AN: 41464

American (AMR) AF: 0.168 AC: 2561 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 641 AN: 3470

East Asian (EAS) AF: 0.152 AC: 784 AN: 5172

South Asian (SAS) AF: 0.259 AC: 1245 AN: 4808

European-Finnish (FIN) AF: 0.113 AC: 1191 AN: 10580

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.141 AC: 9596 AN: 67962

Other (OTH) AF: 0.152 AC: 322 AN: 2112

Alfa AF: 0.121 Hom.: 590

Bravo AF: 0.135

Asia WGS AF: 0.211 AC: 734 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.156

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Immunodeficiency, common variable, 1 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.0
DANN	Benign	0.37
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs4264550; hg19: chr2-204821494; COSMIC: COSV57029989;