rs2229319

Variant names:

• chr16-10907465-C-G
• rs2229319
• NM_000246.4:c.1973C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000246.4(CIITA):​c.1973C>G​(p.Ala658Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,613,500 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A658A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0089 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (21 hom.)
• Consequence: CIITA NM_000246.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.19
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040816665).
• BP6: Variant 16-10907465-C-G is Benign according to our data. Variant chr16-10907465-C-G is described in ClinVar as Benign. ClinVar VariationId is 317701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00887 (1351/152302) while in subpopulation AFR AF = 0.0305 (1269/41576). AF 95% confidence interval is 0.0291. There are 27 homozygotes in GnomAd4. There are 610 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000246.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	NM_000246.4	MANE Select	c.1973C>G	p.Ala658Gly	missense	Exon 11 of 20	NP_000237.2
	CIITA	NM_001286402.1		c.1976C>G	p.Ala659Gly	missense	Exon 11 of 20	NP_001273331.1
	CIITA	NM_001379332.1		c.1976C>G	p.Ala659Gly	missense	Exon 11 of 20	NP_001366261.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	ENST00000324288.14	TSL:1 MANE Select	c.1973C>G	p.Ala658Gly	missense	Exon 11 of 20	ENSP00000316328.8
	CIITA	ENST00000573309.5	TSL:1	n.1944C>G		non_coding_transcript_exon	Exon 10 of 10
	CIITA	ENST00000381835.9	TSL:1	c.860-1518C>G		intron	N/A	ENSP00000371257.5

Frequencies

GnomAD3 genomes AF: 0.00882 AC: 1343 AN: 152184 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00230 AC: 566 AN: 245560 AF XY: 0.00163

Gnomad AFR exome AF: 0.0320

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000547

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.000872 AC: 1274 AN: 1461198 Hom.: 21 Cov.: 67 AF XY: 0.000772 AC XY: 561 AN XY: 726898

African (AFR) AF: 0.0302 AC: 1010 AN: 33478

American (AMR) AF: 0.00201 AC: 90 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52884

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111900

Other (OTH) AF: 0.00214 AC: 129 AN: 60366

GnomAD4 genome AF: 0.00887 AC: 1351 AN: 152302 Hom.: 27 Cov.: 32 AF XY: 0.00819 AC XY: 610 AN XY: 74472

African (AFR) AF: 0.0305 AC: 1269 AN: 41576

American (AMR) AF: 0.00379 AC: 58 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00268 Hom.: 3

Bravo AF: 0.0102

ESP6500AA AF: 0.0251 AC: 110

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00286 AC: 347

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	MHC class II deficiency (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.3
DANN	Benign	0.50
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.90	T
PhyloP100		-1.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Benign	0.34	T
Sift4G	Benign	0.098	T
Vest4		0.18
MVP		0.55
MPC		0.18
ClinPred		0.014	T
GERP RS		-10
gMVP		0.31
Mutation Taster		=97/3	polymorphism

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: rs2229319; hg19: chr16-11001322; COSMIC: COSV99048281; COSMIC: COSV99048281;