Submissions for variant NM_000536.4(RAG2):c.68A>G (p.Asn23Ser)

gnomAD frequency: 0.00001  dbSNP: rs751073669

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765339	SCV005375464	uncertain significance	Recombinase activating gene 2 deficiency	2024-05-01	reviewed by expert panel	curation	NM_000536.4(RAG2):c.68A>G (p.Asn23Ser) is a missense variant predicted to cause substitution of Asparagine by Serine at amino acid 23.This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The filtering allele frequency (the upper threshold of the 95% CI of 11/1180018) of the c.68A>G variant in RAG2 is 0.000004550 for European (Non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting, PM2_supporting (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815023	SCV000955463	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with serine at codon 23 of the RAG2 protein (p.Asn23Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs751073669, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.