2-203955727-A-C

Variant names:

• chr2-203955727-A-C
• NM_012092.4:c.150A>C
• ICOS p.Gln50His

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012092.4(ICOS):​c.150A>C​(p.Gln50His) variant causes a missense 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. Synonymous variant affecting the same amino acid position (i.e. Q50Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ICOS NM_012092.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0390
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26371628).

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.150A>C	p.Gln50His	missense	Exon 2 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.150A>C	p.Gln50His	missense	Exon 2 of 5	ENSP00000319476.6	Q9Y6W8-1
	ICOS	ENST00000435193.1	TSL:1	c.150A>C	p.Gln50His	missense	Exon 2 of 4	ENSP00000415951.1	Q9Y6W8-2
	ICOS	ENST00000897354.1		c.59-932A>C		intron	N/A	ENSP00000567413.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.039
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.020	D
Varity_R		0.42
gMVP		0.91
Mutation Taster		=72/28	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-204820450;