rs10932037

Variant names:

• chr2-203960623-C-T
• rs10932037
• NM_012092.4:c.*1024C>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.*1024C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0814 in 152,276 control chromosomes in the GnomAD database, including 593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (593 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ICOS NM_012092.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.128
• Publications: 25 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=-0.71).
• BP6: Variant 2-203960623-C-T is Benign according to our data. Variant chr2-203960623-C-T is described in ClinVar as Benign. ClinVar VariationId is 333751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0941 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.*1024C>T		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.*1024C>T		3_prime_UTR	Exon 5 of 5	ENSP00000319476.6	Q9Y6W8-1
	ICOS	ENST00000435193.1	TSL:1	c.*1032C>T		3_prime_UTR	Exon 4 of 4	ENSP00000415951.1	Q9Y6W8-2
	ICOS	ENST00000897354.1		c.*1024C>T		3_prime_UTR	Exon 4 of 4	ENSP00000567413.1

Frequencies

GnomAD3 genomes AF: 0.0812 AC: 12355 AN: 152158 Hom.: 586 Cov.: 32

Gnomad AFR AF: 0.0568

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0876

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.0456

Gnomad SAS AF: 0.0588

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0960

Gnomad OTH AF: 0.0712

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

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) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.0814 AC: 12391 AN: 152276 Hom.: 593 Cov.: 32 AF XY: 0.0797 AC XY: 5932 AN XY: 74436

African (AFR) AF: 0.0570 AC: 2367 AN: 41548

American (AMR) AF: 0.0881 AC: 1347 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0501 AC: 174 AN: 3472

East Asian (EAS) AF: 0.0453 AC: 235 AN: 5186

South Asian (SAS) AF: 0.0593 AC: 286 AN: 4824

European-Finnish (FIN) AF: 0.114 AC: 1215 AN: 10612

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0960 AC: 6532 AN: 68018

Other (OTH) AF: 0.0789 AC: 167 AN: 2116

Alfa AF: 0.0896 Hom.: 1194

Bravo AF: 0.0797

Asia WGS AF: 0.0730 AC: 252 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.9
DANN	Benign	0.58
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: rs10932037; hg19: chr2-204825346;