X-71110935-G-C

Variant names:

• chrX-71110935-G-C
• rs1556330951
• NM_000206.3:c.231C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285171 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000206.3. 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
	IL2RG	NM_000206.3	MANE Select	c.231C>G	p.Ser77Arg	missense	Exon 2 of 8	NP_000197.1	P31785-1
	IL2RG	NM_001438870.1		c.231C>G	p.Ser77Arg	missense	Exon 2 of 7	NP_001425799.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	ENST00000374202.7	TSL:1 MANE Select	c.231C>G	p.Ser77Arg	missense	Exon 2 of 8	ENSP00000363318.3	P31785-1
	ENSG00000285171	ENST00000646505.1		n.231C>G		non_coding_transcript_exon	Exon 2 of 12	ENSP00000496673.1	A0A2R8YE73
	IL2RG	ENST00000482750.6	TSL:5	c.231C>G	p.Ser77Arg	missense	Exon 2 of 7	ENSP00000421262.2	H0Y8J6

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

African (AFR) AF: 0.00 AC: 0 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35159

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 53969

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841368

Other (OTH) AF: 0.00 AC: 0 AN: 46060

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.55
Sift	Benign	0.11	T
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
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs1556330951; hg19: chrX-70330785;