rs2229320

Variant names:

• chr16-10907886-G-A
• rs2229320
• NM_000246.4:c.2394G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-10907886-G-A
• chr16-10907886-G-C
• chr16-10907886-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000246.4(CIITA):​c.2394G>A​(p.Pro798Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,600,210 control chromosomes in the GnomAD database, including 35,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P798P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2609 hom., cov: 33)
  • Exomes 𝑓: 0.21 (33191 hom.)
• Consequence: CIITA NM_000246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.40
• Publications: 12 publications found

Genes affected

CIITA (HGNC:7067): (class II major histocompatibility complex transactivator) This gene encodes a protein with an acidic transcriptional activation domain, 4 LRRs (leucine-rich repeats) and a GTP binding domain. The protein is located in the nucleus and acts as a positive regulator of class II major histocompatibility complex gene transcription, and is referred to as the "master control factor" for the expression of these genes. The protein also binds GTP and uses GTP binding to facilitate its own transport into the nucleus. Once in the nucleus it does not bind DNA but rather uses an intrinsic acetyltransferase (AT) activity to act in a coactivator-like fashion. Mutations in this gene have been associated with bare lymphocyte syndrome type II (also known as hereditary MHC class II deficiency or HLA class II-deficient combined immunodeficiency), increased susceptibility to rheumatoid arthritis, multiple sclerosis, and possibly myocardial infarction. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

CIITA Gene-Disease associations (from GenCC):

• MHC class II deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000308110 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-10907886-G-A is Benign according to our data. Variant chr16-10907886-G-A is described in ClinVar as Benign. ClinVar VariationId is 317710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.2394G>A	p.Pro798Pro	synonymous_variant	Exon 11 of 20	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.2394G>A	p.Pro798Pro	synonymous_variant	Exon 11 of 20	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25467 AN: 152108 Hom.: 2606 Cov.: 33

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.176

GnomAD2 exomes AF: 0.211 AC: 49961 AN: 236446 AF XY: 0.219

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.314

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.210 AC: 303453 AN: 1447984 Hom.: 33191 Cov.: 82 AF XY: 0.212 AC XY: 152615 AN XY: 719124

African (AFR) AF: 0.0425 AC: 1401 AN: 32956

American (AMR) AF: 0.147 AC: 6353 AN: 43352

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5432 AN: 25056

East Asian (EAS) AF: 0.295 AC: 11663 AN: 39558

South Asian (SAS) AF: 0.280 AC: 23576 AN: 84250

European-Finnish (FIN) AF: 0.253 AC: 13287 AN: 52552

Middle Eastern (MID) AF: 0.235 AC: 1328 AN: 5662

European-Non Finnish (NFE) AF: 0.207 AC: 228564 AN: 1104866

Other (OTH) AF: 0.198 AC: 11849 AN: 59732

GnomAD4 genome AF: 0.167 AC: 25470 AN: 152226 Hom.: 2609 Cov.: 33 AF XY: 0.171 AC XY: 12745 AN XY: 74406

African (AFR) AF: 0.0490 AC: 2039 AN: 41578

American (AMR) AF: 0.159 AC: 2428 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 728 AN: 3472

East Asian (EAS) AF: 0.302 AC: 1557 AN: 5158

South Asian (SAS) AF: 0.285 AC: 1377 AN: 4824

European-Finnish (FIN) AF: 0.254 AC: 2682 AN: 10578

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13948 AN: 67992

Other (OTH) AF: 0.174 AC: 367 AN: 2112

Alfa AF: 0.183 Hom.: 1325

Bravo AF: 0.154

Asia WGS AF: 0.219 AC: 764 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:4

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.055
DANN	Benign	0.65
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2229320; hg19: chr16-11001743; COSMIC: COSV60853804;