chr2-203960563-T-C

Variant names:

• chr2-203960563-T-C
• rs4404254
• NM_012092.4:c.*964T>C

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.*964T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 152,192 control chromosomes in the GnomAD database, including 7,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7116 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: ICOS NM_012092.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.316
• Publications: 35 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=-0.91).
• BP6: Variant 2-203960563-T-C is Benign according to our data. Variant chr2-203960563-T-C is described in ClinVar as Benign. ClinVar VariationId is 333747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 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.*964T>C		3_prime_UTR	Exon 5 of 5	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.*964T>C		3_prime_UTR	Exon 5 of 5	ENSP00000319476.6	Q9Y6W8-1
	ICOS	ENST00000435193.1	TSL:1	c.*972T>C		3_prime_UTR	Exon 4 of 4	ENSP00000415951.1	Q9Y6W8-2
	ICOS	ENST00000897354.1		c.*964T>C		3_prime_UTR	Exon 4 of 4	ENSP00000567413.1

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44419 AN: 152074 Hom.: 7082 Cov.: 32

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.287

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.292 AC: 44509 AN: 152192 Hom.: 7116 Cov.: 32 AF XY: 0.292 AC XY: 21729 AN XY: 74410

African (AFR) AF: 0.412 AC: 17085 AN: 41494

American (AMR) AF: 0.290 AC: 4427 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 827 AN: 3472

East Asian (EAS) AF: 0.197 AC: 1024 AN: 5186

South Asian (SAS) AF: 0.344 AC: 1659 AN: 4826

European-Finnish (FIN) AF: 0.227 AC: 2403 AN: 10596

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16214 AN: 68020

Other (OTH) AF: 0.292 AC: 617 AN: 2112

Alfa AF: 0.260 Hom.: 7333

Bravo AF: 0.299

Asia WGS AF: 0.309 AC: 1077 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.1
DANN	Benign	0.55
PhyloP100		0.32
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: rs4404254; hg19: chr2-204825286;