2-203936831-G-A

Variant names:

• chr2-203936831-G-A
• NM_012092.4:c.17G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_012092.4(ICOS):​c.17G>A​(p.Trp6*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ICOS NM_012092.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.27
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-203936831-G-A is Pathogenic according to our data. Variant chr2-203936831-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2002817.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICOS	NM_012092.4	c.17G>A	p.Trp6*	stop_gained	Exon 1 of 5	ENST00000316386.11	NP_036224.1
ICOS	XR_007073112.1	n.69G>A		non_coding_transcript_exon_variant	Exon 1 of 6
LOC101927840	XR_427213.4	n.314+486C>T		intron_variant	Intron 2 of 3
ICOS	XM_047444022.1	c.-3604G>A		upstream_gene_variant			XP_047299978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.17G>A	p.Trp6*	stop_gained	Exon 1 of 5	1	NM_012092.4	ENSP00000319476.6
ICOS	ENST00000435193.1	c.17G>A	p.Trp6*	stop_gained	Exon 1 of 4	1		ENSP00000415951.1
ENSG00000300710	ENST00000773540.1	n.183+486C>T		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency, common variable, 1 Pathogenic:1

Jun 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with ICOS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp6*) in the ICOS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ICOS are known to be pathogenic (PMID: 11343122, 12577056, 19380800). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Benign	0.70	D
PhyloP100		2.3
Vest4		0.85
GERP RS		4.6
PromoterAI		-0.10	Neutral
Mutation Taster		=100/100	disease causing (fs/PTC)

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

hg19: chr2-204801554;