rs10932037

chr2-203960623-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 0.128

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 333751.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICOS	NM_012092.4	c.*1024C>T		3_prime_UTR_variant	5/5	ENST00000316386.11
ICOS	XM_047444022.1	c.*1024C>T		3_prime_UTR_variant	5/5
ICOS	XR_007073112.1	n.1789C>T		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICOS	ENST00000316386.11	c.*1024C>T		3_prime_UTR_variant	5/5	1	NM_012092.4	P2
ICOS	ENST00000435193.1	c.*1032C>T		3_prime_UTR_variant	4/4	1		A2

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

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.0570

Gnomad4 AMR AF: 0.0881

Gnomad4 ASJ AF: 0.0501

Gnomad4 EAS AF: 0.0453

Gnomad4 SAS AF: 0.0593

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0960

Gnomad4 OTH AF: 0.0789

Alfa AF: 0.0897 Hom.: 867

Bravo AF: 0.0797

Asia WGS AF: 0.0730 AC: 252 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency, common variable, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	8.9
Dann	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs10932037; hg19: chr2-204825346;