chr2-203936831-G-A

Position:

• chr2-203936831-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_012092.4(ICOS):​c.17G>A​(p.Trp6Ter) 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

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]

LOC101927840 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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. Fraction of 0.972 CDS is truncated, and there are 0 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/exons	MANE	Protein	UniProt
ICOS	NM_012092.4	c.17G>A	p.Trp6Ter	stop_gained	1/5	ENST00000316386.11	NP_036224.1
LOC101927840	XR_427213.4	n.314+486C>T		intron_variant, non_coding_transcript_variant
ICOS	XR_007073112.1	n.69G>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11	c.17G>A	p.Trp6Ter	stop_gained	1/5	1	NM_012092.4	ENSP00000319476	P2
ICOS	ENST00000435193.1	c.17G>A	p.Trp6Ter	stop_gained	1/4	1		ENSP00000415951	A2

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 08, 2022

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
MutationTaster	Benign	1.0	A;A
Vest4		0.85
GERP RS		4.6

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-204801554;