chr2-203961372-G-C

Variant names:

• chr2-203961372-G-C
• rs4675379
• NM_012092.4:c.*1773G>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.*1773G>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 0.15 in 174,490 control chromosomes in the GnomAD database, including 2,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1882 hom., cov: 30)
  • Exomes 𝑓: 0.13 (186 hom.)
• Consequence: ICOS NM_012092.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.26
• Publications: 21 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=-0.92).
• BP6: Variant 2-203961372-G-C is Benign according to our data. Variant chr2-203961372-G-C is described in ClinVar as Benign. ClinVar VariationId is 333760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.27 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.*1773G>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.*1773G>C		3_prime_UTR	Exon 5 of 5	ENSP00000319476.6	Q9Y6W8-1
	ICOS	ENST00000435193.1	TSL:1	c.*1781G>C		3_prime_UTR	Exon 4 of 4	ENSP00000415951.1	Q9Y6W8-2
	ICOS	ENST00000897354.1		c.*1773G>C		3_prime_UTR	Exon 4 of 4	ENSP00000567413.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23231 AN: 151388 Hom.: 1873 Cov.: 30

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.168

GnomAD4 exome AF: 0.125 AC: 2882 AN: 22984 Hom.: 186 Cov.: 0 AF XY: 0.125 AC XY: 1508 AN XY: 12070

African (AFR) AF: 0.116 AC: 58 AN: 500

American (AMR) AF: 0.155 AC: 77 AN: 498

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 86 AN: 660

East Asian (EAS) AF: 0.137 AC: 364 AN: 2654

South Asian (SAS) AF: 0.257 AC: 56 AN: 218

European-Finnish (FIN) AF: 0.0791 AC: 226 AN: 2858

Middle Eastern (MID) AF: 0.225 AC: 23 AN: 102

European-Non Finnish (NFE) AF: 0.127 AC: 1817 AN: 14310

Other (OTH) AF: 0.148 AC: 175 AN: 1184

GnomAD4 genome AF: 0.153 AC: 23255 AN: 151506 Hom.: 1882 Cov.: 30 AF XY: 0.156 AC XY: 11546 AN XY: 74006

African (AFR) AF: 0.159 AC: 6567 AN: 41228

American (AMR) AF: 0.175 AC: 2661 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 605 AN: 3468

East Asian (EAS) AF: 0.152 AC: 787 AN: 5164

South Asian (SAS) AF: 0.283 AC: 1348 AN: 4764

European-Finnish (FIN) AF: 0.112 AC: 1179 AN: 10530

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

European-Non Finnish (NFE) AF: 0.141 AC: 9580 AN: 67866

Other (OTH) AF: 0.166 AC: 349 AN: 2104

Alfa AF: 0.0635 Hom.: 57

Bravo AF: 0.154

Asia WGS AF: 0.223 AC: 775 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	-0.92
CADD	Benign	0.32
DANN	Benign	0.40
PhyloP100		-2.3
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: rs4675379; hg19: chr2-204826095;