2-203937045-T-C

Variant names:

• chr2-203937045-T-C
• rs10932029
• NM_012092.4:c.58+173T>C

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.58+173T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,124 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.11 (1261 hom., cov: 32)
• Consequence: ICOS NM_012092.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.18
• Publications: 19 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000300710 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 2-203937045-T-C is Benign according to our data. Variant chr2-203937045-T-C is described in ClinVar as [Benign]. Clinvar id is 1275514.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICOS	NM_012092.4	c.58+173T>C		intron_variant	Intron 1 of 4	ENST00000316386.11	NP_036224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.58+173T>C		intron_variant	Intron 1 of 4	1	NM_012092.4	ENSP00000319476.6
ICOS	ENST00000435193.1	c.58+173T>C		intron_variant	Intron 1 of 3	1		ENSP00000415951.1
ENSG00000300710	ENST00000773540.1	n.183+272A>G		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17368 AN: 152006 Hom.: 1256 Cov.: 32

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.139

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.114 AC: 17376 AN: 152124 Hom.: 1261 Cov.: 32 AF XY: 0.114 AC XY: 8460 AN XY: 74384

African (AFR) AF: 0.0303 AC: 1256 AN: 41512

American (AMR) AF: 0.141 AC: 2149 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 544 AN: 3466

East Asian (EAS) AF: 0.131 AC: 675 AN: 5166

South Asian (SAS) AF: 0.173 AC: 830 AN: 4808

European-Finnish (FIN) AF: 0.120 AC: 1265 AN: 10576

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10289 AN: 67996

Other (OTH) AF: 0.136 AC: 288 AN: 2110

Alfa AF: 0.123 Hom.: 689

Bravo AF: 0.111

Asia WGS AF: 0.155 AC: 538 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.8
DANN	Benign	0.81
PhyloP100		-1.2
PromoterAI		0.024	Neutral
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: rs10932029; hg19: chr2-204801768;