21-44229035-C-G

Variant names:

• chr21-44229035-C-G
• rs746057000
• NM_015259.6:c.908G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_015259.6(ICOSLG):​c.908G>C​(p.Ter303Serext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: ICOSLG NM_015259.6 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Stoplost variant in NM_015259.6 Downstream stopcodon found after 344 codons.

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.908G>C	p.Ter303Serext*?	stop_lost	Exon 7 of 7	NP_056074.1	O75144-1
	ICOSLG	NM_001365759.2		c.827G>C	p.Ter276Serext*?	stop_lost	Exon 7 of 7	NP_001352688.1
	ICOSLG	NM_001283052.2		c.653G>C	p.Ter218Serext*?	stop_lost	Exon 7 of 7	NP_001269981.1	B7Z1W8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.908G>C	p.Ter303Serext*?	stop_lost	Exon 7 of 7	ENSP00000384432.3	O75144-1
	ICOSLG	ENST00000400379.8	TSL:1	c.*495G>C		3_prime_UTR	Exon 6 of 6	ENSP00000383230.3	K4DIA0
	ICOSLG	ENST00000344330.9	TSL:1	c.898+1019G>C		intron	N/A	ENSP00000339477.4	O75144-2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000725 AC: 18 AN: 248140 AF XY: 0.0000964

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

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 Cov.: 4

GnomAD4 genome Cov.: 0

ExAC AF: 0.0000661 AC: 8

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
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.2
DANN	Benign	0.76
Eigen	Uncertain	0.34
Eigen_PC	Benign	-0.048
FATHMM_MKL	Benign	0.27	N
PhyloP100		1.5
Vest4		0.093
GERP RS		2.5
Mutation Taster		=81/119	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs746057000; hg19: chr21-45648918; COSMIC: COSV60265489;