X-71110935-G-C

Position:

• chrX-71110935-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000206.3(IL2RG):​c.231C>G​(p.Ser77Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,147 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S77S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000206.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL2RG	NM_000206.3	c.231C>G	p.Ser77Arg	missense_variant	2/8	ENST00000374202.7
IL2RG	XM_047442089.1	c.231C>G	p.Ser77Arg	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RG	ENST00000374202.7	c.231C>G	p.Ser77Arg	missense_variant	2/8	1	NM_000206.3	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097147 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362525

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.;T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.11	T;T;D
Sift4G	Uncertain	0.035	D;.;.
Polyphen		0.73	P;.;.
Vest4		0.39
MutPred		0.40		Gain of catalytic residue at S77 (P = 0.0201);.;.;
MVP		0.99
MPC		0.77
ClinPred		0.84	D
GERP RS		4.6
Varity_R		0.75
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 1
DS_DL_spliceai		0.22		Position offset: -38

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556330951; hg19: chrX-70330785;