11-36595228-C-T

Variant names:

• chr11-36595228-C-T
• rs11033703
• NM_000536.4:c.-27-1033G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000536.4(RAG2):​c.-27-1033G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 152,080 control chromosomes in the GnomAD database, including 1,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1435 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: RAG2 NM_000536.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0200

Genes affected

RAG2 (HGNC:9832): (recombination activating 2) This gene encodes a protein that is involved in the initiation of V(D)J recombination during B and T cell development. This protein forms a complex with the product of the adjacent recombination activating gene 1, and this complex can form double-strand breaks by cleaving DNA at conserved recombination signal sequences. The recombination activating gene 1 component is thought to contain most of the catalytic activity, while the N-terminal of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. A C-terminal plant homeodomain finger-like motif in this protein is necessary for interactions with chromatin components, specifically with histone H3 that is trimethylated at lysine 4. Mutations in this gene cause Omenn syndrome, a form of severe combined immunodeficiency associated with autoimmune-like symptoms. [provided by RefSeq, Jul 2008]

IFTAP (HGNC:25142): (intraflagellar transport associated protein) This gene encodes a protein that was identified as a cellular interacting partner of non-structural protein 10 of the severe acute respiratory syndrome coronavirus (SARS-CoV). The encoded protein may function as a negative regulator of transcription. There is a pseudogene for this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-36595228-C-T is Benign according to our data. Variant chr11-36595228-C-T is described in ClinVar as [Benign]. Clinvar id is 1245703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG2	NM_000536.4	c.-27-1033G>A		intron_variant	Intron 1 of 1	ENST00000311485.8	NP_000527.2
IFTAP	NM_138787.4	c.-24+636C>T		intron_variant	Intron 1 of 5	ENST00000334307.10	NP_620142.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAG2	ENST00000311485.8	c.-27-1033G>A		intron_variant	Intron 1 of 1	1	NM_000536.4	ENSP00000308620.4
IFTAP	ENST00000334307.10	c.-24+636C>T		intron_variant	Intron 1 of 5	1	NM_138787.4	ENSP00000334848.5

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20051 AN: 151960 Hom.: 1434 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0779

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.132 AC: 20060 AN: 152078 Hom.: 1435 Cov.: 32 AF XY: 0.133 AC XY: 9921 AN XY: 74346

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.0775

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.127

Alfa AF: 0.128 Hom.: 195

Bravo AF: 0.139

Asia WGS AF: 0.137 AC: 478 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.1
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11033703; hg19: chr11-36616778;