NM_000206.3:c.*290T>C

Variant names:

• chrX-71107446-A-G
• rs763003140
• NM_000206.3:c.*290T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000206.3(IL2RG):​c.*290T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000997 in 260,713 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 10 hem., cov: 23)
  • Exomes 𝑓: 0.000087 (0 hom. 7 hem.)
• Consequence: IL2RG NM_000206.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.26
• Publications: 0 publications found

Genes affected

IL2RG (HGNC:6010): (interleukin 2 receptor subunit gamma) The protein encoded by this gene is an important signaling component of many interleukin receptors, including those of interleukin -2, -4, -7 and -21, and is thus referred to as the common gamma chain. Mutations in this gene cause X-linked severe combined immunodeficiency (XSCID), as well as X-linked combined immunodeficiency (XCID), a less severe immunodeficiency disorder. [provided by RefSeq, Mar 2010]

IL2RG Gene-Disease associations (from GenCC):

• T-B+ severe combined immunodeficiency due to gamma chain deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285171 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-71107446-A-G is Benign according to our data. Variant chrX-71107446-A-G is described in ClinVar as [Benign]. Clinvar id is 368615.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000117 (13/111455) while in subpopulation SAS AF = 0.00491 (13/2646). AF 95% confidence interval is 0.00291. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 10 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.*290T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000374202.7	NP_000197.1
IL2RG	NM_001438870.1	c.*520T>C		3_prime_UTR_variant	Exon 7 of 7		NP_001425799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.*290T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.925-676T>C		intron_variant	Intron 7 of 11			ENSP00000496673.1

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111405 Hom.: 0 Cov.: 23

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: 0.00489

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000871 AC: 13 AN: 149258 Hom.: 0 Cov.: 0 AF XY: 0.000186 AC XY: 7 AN XY: 37692

African (AFR) AF: 0.00 AC: 0 AN: 4887

American (AMR) AF: 0.00 AC: 0 AN: 5482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5320

East Asian (EAS) AF: 0.00 AC: 0 AN: 13441

South Asian (SAS) AF: 0.00503 AC: 12 AN: 2386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 731

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 94053

Other (OTH) AF: 0.0000958 AC: 1 AN: 10435

GnomAD4 genome AF: 0.000117 AC: 13 AN: 111455 Hom.: 0 Cov.: 23 AF XY: 0.000297 AC XY: 10 AN XY: 33645

African (AFR) AF: 0.00 AC: 0 AN: 30633

American (AMR) AF: 0.00 AC: 0 AN: 10525

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00491 AC: 13 AN: 2646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6007

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53043

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked severe combined immunodeficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.036
DANN	Benign	0.60
PhyloP100		-1.3

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: rs763003140; hg19: chrX-70327296;