NM_000206.3:c.1080C>T

Variant names:

• chrX-71107766-G-A
• rs748015056
• NM_000206.3:c.1080C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_000206.3(IL2RG):​c.1080C>T​(p.Pro360Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,150,755 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P360P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000023 (0 hom. 8 hem.)
• Consequence: IL2RG NM_000206.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.51
• Publications: 2 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-71107766-G-A is Benign according to our data. Variant chrX-71107766-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1158161.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000231 (24/1038425) while in subpopulation MID AF = 0.000521 (2/3842). AF 95% confidence interval is 0.0000922. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 8 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.1080C>T	p.Pro360Pro	synonymous_variant	Exon 8 of 8	ENST00000374202.7	NP_000197.1
IL2RG	NM_001438870.1	c.*200C>T		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.1080C>T	p.Pro360Pro	synonymous_variant	Exon 8 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.924+511C>T		intron_variant	Intron 7 of 11			ENSP00000496673.1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112330 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000150 AC: 2 AN: 133664 AF XY: 0.0000235

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: 0.0000314

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000231 AC: 24 AN: 1038425 Hom.: 0 Cov.: 29 AF XY: 0.0000241 AC XY: 8 AN XY: 332631

African (AFR) AF: 0.00 AC: 0 AN: 24132

American (AMR) AF: 0.00 AC: 0 AN: 24536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15646

East Asian (EAS) AF: 0.00 AC: 0 AN: 29586

South Asian (SAS) AF: 0.00 AC: 0 AN: 45280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38349

Middle Eastern (MID) AF: 0.000521 AC: 2 AN: 3842

European-Non Finnish (NFE) AF: 0.0000258 AC: 21 AN: 813654

Other (OTH) AF: 0.0000230 AC: 1 AN: 43400

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112330 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34490

African (AFR) AF: 0.00 AC: 0 AN: 30865

American (AMR) AF: 0.00 AC: 0 AN: 10739

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6177

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53181

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked severe combined immunodeficiency Benign:1

Sep 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.58
DANN	Benign	0.35
PhyloP100		-2.5
Mutation Taster		=100/0	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: rs748015056; hg19: chrX-70327616;