rs2228238

Variant names:

• chr16-10909047-G-A
• rs2228238
• NM_000246.4:c.2676G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-10909047-G-A
• chr16-10909047-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000246.4(CIITA):​c.2676G>A​(p.Thr892Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,613,932 control chromosomes in the GnomAD database, including 395,596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33146 hom., cov: 33)
  • Exomes 𝑓: 0.70 (362450 hom.)
• Consequence: CIITA NM_000246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.65

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-10909047-G-A is Benign according to our data. Variant chr16-10909047-G-A is described in ClinVar as [Benign]. Clinvar id is 317717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-10909047-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.2676G>A	p.Thr892Thr	synonymous_variant	Exon 12 of 20	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.2676G>A	p.Thr892Thr	synonymous_variant	Exon 12 of 20	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes AF: 0.653 AC: 99256 AN: 152020 Hom.: 33143 Cov.: 33

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.669

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.680

GnomAD3 exomes AF: 0.682 AC: 171164 AN: 250960 Hom.: 59720 AF XY: 0.695 AC XY: 94314 AN XY: 135748

Gnomad AFR exome AF: 0.508

Gnomad AMR exome AF: 0.505

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.854

Gnomad SAS exome AF: 0.729

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.703

Gnomad OTH exome AF: 0.689

GnomAD4 exome AF: 0.702 AC: 1025914 AN: 1461794 Hom.: 362450 Cov.: 66 AF XY: 0.704 AC XY: 512031 AN XY: 727192

Gnomad4 AFR exome AF: 0.508

Gnomad4 AMR exome AF: 0.514

Gnomad4 ASJ exome AF: 0.708

Gnomad4 EAS exome AF: 0.793

Gnomad4 SAS exome AF: 0.735

Gnomad4 FIN exome AF: 0.756

Gnomad4 NFE exome AF: 0.707

Gnomad4 OTH exome AF: 0.690

GnomAD4 genome AF: 0.653 AC: 99294 AN: 152138 Hom.: 33146 Cov.: 33 AF XY: 0.655 AC XY: 48714 AN XY: 74392

Gnomad4 AFR AF: 0.517

Gnomad4 AMR AF: 0.601

Gnomad4 ASJ AF: 0.717

Gnomad4 EAS AF: 0.841

Gnomad4 SAS AF: 0.744

Gnomad4 FIN AF: 0.770

Gnomad4 NFE AF: 0.703

Gnomad4 OTH AF: 0.677

Alfa AF: 0.678 Hom.: 17782

Bravo AF: 0.631

Asia WGS AF: 0.720 AC: 2505 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.58
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2228238; hg19: chr16-11002904; COSMIC: COSV60862367; COSMIC: COSV60862367;