Genetic Variant ICOS:c.501+126C>A (chr2-203956891-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012092.4(ICOS):c.501+126C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ICOS
NM_012092.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.48

Publications

6 publications found

Variant links:

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)

ICOS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ICOS	NM_012092.4 link	c.501+126C>A	intron_variant	Intron 3 of 4	ENST00000316386.11	NP_036224.1	Q9Y6W8-1Q53QY6
ICOS	XM_047444022.1 link	c.504+126C>A	intron_variant	Intron 3 of 4		XP_047299978.1
ICOS	XR_007073112.1 link	n.553+126C>A	intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOS	ENST00000316386.11 link	c.501+126C>A		intron_variant	Intron 3 of 4	1	NM_012092.4	ENSP00000319476.6		Q9Y6W8-1
ICOS	ENST00000435193.1 link	c.501+126C>A		intron_variant	Intron 3 of 3	1		ENSP00000415951.1		Q9Y6W8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

544936

Hom.:

AF XY:

0.00

AC XY:

AN XY:

292486

African (AFR)

AF:

0.00

AC:

AN:

15246

American (AMR)

AF:

0.00

AC:

AN:

33090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19012

East Asian (EAS)

AF:

0.00

AC:

AN:

31334

South Asian (SAS)

AF:

0.00

AC:

AN:

60572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2388

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

313094

Other (OTH)

AF:

0.00

AC:

AN:

29450

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.29

(source)

DANN

Benign

0.78

PhyloP100

-1.5

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over