chr21-44230041-AC-A

Variant names:

• chr21-44230041-AC-A
• rs753701173
• ENST00000400379.8:c.910delG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The ENST00000400379.8(ICOSLG):​c.910delG​(p.Val304TrpfsTer250) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 9)
  • Exomes 𝑓: 0.00025 (29 hom.)
  • Failed GnomAD Quality Control
• Consequence: ICOSLG ENST00000400379.8 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.77
• 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 21-44230041-AC-A is Benign according to our data. Variant chr21-44230041-AC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1104881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000400379.8. 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.898+12delG		intron	N/A	NP_056074.1	O75144-1
	ICOSLG	NM_001283050.2		c.898+12delG		intron	N/A	NP_001269979.1	O75144-2
	ICOSLG	NM_001395918.1		c.898+12delG		intron	N/A	NP_001382847.1	A0A8V8TQV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	ENST00000400379.8	TSL:1	c.910delG	p.Val304TrpfsTer250	frameshift	Exon 6 of 6	ENSP00000383230.3	K4DIA0
	ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.898+12delG		intron	N/A	ENSP00000384432.3	O75144-1
	ICOSLG	ENST00000344330.9	TSL:1	c.898+12delG		intron	N/A	ENSP00000339477.4	O75144-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 1 AN: 76076 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000306

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000738 AC: 116 AN: 157126 AF XY: 0.000672

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000281

Gnomad ASJ exome AF: 0.000237

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000653

Gnomad NFE exome AF: 0.00159

Gnomad OTH exome AF: 0.000685

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000248 AC: 181 AN: 729476 Hom.: 29 Cov.: 9 AF XY: 0.000250 AC XY: 91 AN XY: 364002

African (AFR) AF: 0.0000960 AC: 2 AN: 20838

American (AMR) AF: 0.000110 AC: 2 AN: 18252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14420

East Asian (EAS) AF: 0.00 AC: 0 AN: 26720

South Asian (SAS) AF: 0.000234 AC: 12 AN: 51366

European-Finnish (FIN) AF: 0.000198 AC: 4 AN: 20248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3822

European-Non Finnish (NFE) AF: 0.000266 AC: 144 AN: 540496

Other (OTH) AF: 0.000510 AC: 17 AN: 33314

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000131 AC: 1 AN: 76126 Hom.: 0 Cov.: 9 AF XY: 0.0000271 AC XY: 1 AN XY: 36886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22328

American (AMR) AF: 0.00 AC: 0 AN: 7508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1956

East Asian (EAS) AF: 0.00 AC: 0 AN: 3234

South Asian (SAS) AF: 0.00 AC: 0 AN: 2618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 198

European-Non Finnish (NFE) AF: 0.0000306 AC: 1 AN: 32688

Other (OTH) AF: 0.00 AC: 0 AN: 1076

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000632 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.8
Mutation Taster		=116/84	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

Other links and lift over

dbSNP: rs753701173; hg19: chr21-45649924;