NM_000246.4:c.2472C>T

Variant names:

• chr16-10907964-C-T
• rs45621432
• NM_000246.4:c.2472C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000246.4(CIITA):​c.2472C>T​(p.His824His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,570,188 control chromosomes in the GnomAD database, including 672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (46 hom., cov: 33)
  • Exomes 𝑓: 0.026 (626 hom.)
• Consequence: CIITA NM_000246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.30
• Publications: 7 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=-0.64).
• BP6: Variant 16-10907964-C-T is Benign according to our data. Variant chr16-10907964-C-T is described in ClinVar as Benign. ClinVar VariationId is 317713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0192 (2922/152322) while in subpopulation NFE AF = 0.0256 (1740/68022). AF 95% confidence interval is 0.0246. There are 46 homozygotes in GnomAd4. There are 1524 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.2472C>T	p.His824His	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.2472C>T	p.His824His	synonymous_variant	Exon 11 of 20	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2922 AN: 152204 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00477

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.00876

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0720

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0214 AC: 4608 AN: 215586 AF XY: 0.0214

Gnomad AFR exome AF: 0.00561

Gnomad AMR exome AF: 0.00823

Gnomad ASJ exome AF: 0.00825

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0746

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0198

GnomAD4 exome AF: 0.0258 AC: 36585 AN: 1417866 Hom.: 626 Cov.: 36 AF XY: 0.0252 AC XY: 17629 AN XY: 700630

African (AFR) AF: 0.00434 AC: 139 AN: 32030

American (AMR) AF: 0.00862 AC: 338 AN: 39216

Ashkenazi Jewish (ASJ) AF: 0.00876 AC: 202 AN: 23060

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39282

South Asian (SAS) AF: 0.000700 AC: 55 AN: 78604

European-Finnish (FIN) AF: 0.0704 AC: 3624 AN: 51474

Middle Eastern (MID) AF: 0.00271 AC: 15 AN: 5528

European-Non Finnish (NFE) AF: 0.0284 AC: 30934 AN: 1090392

Other (OTH) AF: 0.0219 AC: 1276 AN: 58280

GnomAD4 genome AF: 0.0192 AC: 2922 AN: 152322 Hom.: 46 Cov.: 33 AF XY: 0.0205 AC XY: 1524 AN XY: 74486

African (AFR) AF: 0.00476 AC: 198 AN: 41588

American (AMR) AF: 0.00875 AC: 134 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.0720 AC: 763 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0256 AC: 1740 AN: 68022

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.0191 Hom.: 10

Bravo AF: 0.0146

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:3

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

- -

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. -

CIITA-related disorder Benign:1

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	-0.64
CADD	Benign	2.1
DANN	Benign	0.40
PhyloP100		-1.3
Mutation Taster		=99/1	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: rs45621432; hg19: chr16-11001821;