rs1161445658

Variant names:

• chr21-44230068-T-C
• rs1161445658
• NM_015259.6:c.884A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015259.6(ICOSLG):​c.884A>G​(p.Glu295Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 9)
  • Exomes 𝑓: 0.000016 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: ICOSLG NM_015259.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.459
• Publications: 0 publications found

Genes affected

ICOSLG (HGNC:17087): (inducible T cell costimulator ligand) Enables identical protein binding activity. Predicted to be involved in T cell receptor signaling pathway and positive regulation of interleukin-4 production. Located in cytoplasmic ribonucleoprotein granule and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ICOSLG Gene-Disease associations (from GenCC):

• combined immunodeficiency

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• immunodeficiency 119

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.12327579).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015259.6. 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
	ICOSLG	NM_015259.6	MANE Select	c.884A>G	p.Glu295Gly	missense	Exon 6 of 7	NP_056074.1	O75144-1
	ICOSLG	NM_001283050.2		c.884A>G	p.Glu295Gly	missense	Exon 6 of 7	NP_001269979.1	O75144-2
	ICOSLG	NM_001395918.1		c.884A>G	p.Glu295Gly	missense	Exon 6 of 7	NP_001382847.1	A0A8V8TQV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.884A>G	p.Glu295Gly	missense	Exon 6 of 7	ENSP00000384432.3	O75144-1
	ICOSLG	ENST00000400379.8	TSL:1	c.884A>G	p.Glu295Gly	missense	Exon 6 of 6	ENSP00000383230.3	K4DIA0
	ICOSLG	ENST00000344330.9	TSL:1	c.884A>G	p.Glu295Gly	missense	Exon 6 of 7	ENSP00000339477.4	O75144-2

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD2 exomes AF: 0.00 AC: 0 AN: 155972 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000157 AC: 11 AN: 700126 Hom.: 4 Cov.: 7 AF XY: 0.0000202 AC XY: 7 AN XY: 346760

African (AFR) AF: 0.00 AC: 0 AN: 19710

American (AMR) AF: 0.00 AC: 0 AN: 16392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13370

East Asian (EAS) AF: 0.00 AC: 0 AN: 24210

South Asian (SAS) AF: 0.00 AC: 0 AN: 47176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3712

European-Non Finnish (NFE) AF: 0.0000209 AC: 11 AN: 525478

Other (OTH) AF: 0.00 AC: 0 AN: 31922

GnomAD4 genome Cov.: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.46
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.048
Sift	Benign	0.085	T
Sift4G	Uncertain	0.058	T
Polyphen		0.98	D
Vest4		0.18
MutPred		0.15		Loss of catalytic residue at E295 (P = 0.0696)
MVP		0.29
MPC		1.3
ClinPred		0.44	T
GERP RS		1.6
PromoterAI		-0.021	Neutral
Varity_R		0.14
gMVP		0.47
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1161445658; hg19: chr21-45649951;