rs2229322

Variant names:

• chr16-10922188-C-T
• rs2229322
• NM_000246.4:c.3171C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-10922188-C-T
• chr16-10922188-C-A

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.3171C>T​(p.Cys1057Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,726 control chromosomes in the GnomAD database, including 9,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (737 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9028 hom.)
• Consequence: CIITA NM_000246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.73
• Publications: 15 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 16-10922188-C-T is Benign according to our data. Variant chr16-10922188-C-T is described in ClinVar as Benign. ClinVar VariationId is 317725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	NM_000246.4	MANE Select	c.3171C>T	p.Cys1057Cys	synonymous	Exon 17 of 20	NP_000237.2
	CIITA	NM_001286402.1		c.3174C>T	p.Cys1058Cys	synonymous	Exon 17 of 20	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.3174C>T	p.Cys1058Cys	synonymous	Exon 17 of 20	NP_001366261.1	A0A087X2I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	ENST00000324288.14	TSL:1 MANE Select	c.3171C>T	p.Cys1057Cys	synonymous	Exon 17 of 20	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.1419C>T	p.Cys473Cys	synonymous	Exon 15 of 18	ENSP00000371257.5	P33076-3
	CIITA	ENST00000886127.1		c.3273C>T	p.Cys1091Cys	synonymous	Exon 18 of 21	ENSP00000556186.1

Frequencies

GnomAD3 genomes AF: 0.0975 AC: 14834 AN: 152178 Hom.: 738 Cov.: 33

Gnomad AFR AF: 0.0738

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0772

Gnomad FIN AF: 0.0943

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.103 AC: 25921 AN: 251430 AF XY: 0.103

Gnomad AFR exome AF: 0.0748

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0994

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.0962

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.108 AC: 158382 AN: 1461430 Hom.: 9028 Cov.: 33 AF XY: 0.108 AC XY: 78600 AN XY: 727050

African (AFR) AF: 0.0686 AC: 2296 AN: 33474

American (AMR) AF: 0.105 AC: 4702 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0965 AC: 2523 AN: 26136

East Asian (EAS) AF: 0.156 AC: 6201 AN: 39698

South Asian (SAS) AF: 0.0866 AC: 7470 AN: 86238

European-Finnish (FIN) AF: 0.0958 AC: 5116 AN: 53414

Middle Eastern (MID) AF: 0.107 AC: 620 AN: 5768

European-Non Finnish (NFE) AF: 0.110 AC: 122490 AN: 1111602

Other (OTH) AF: 0.115 AC: 6964 AN: 60380

GnomAD4 genome AF: 0.0974 AC: 14833 AN: 152296 Hom.: 737 Cov.: 33 AF XY: 0.0973 AC XY: 7249 AN XY: 74468

African (AFR) AF: 0.0737 AC: 3062 AN: 41570

American (AMR) AF: 0.121 AC: 1848 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 336 AN: 3470

East Asian (EAS) AF: 0.168 AC: 868 AN: 5166

South Asian (SAS) AF: 0.0767 AC: 370 AN: 4826

European-Finnish (FIN) AF: 0.0943 AC: 1000 AN: 10610

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6919 AN: 68036

Other (OTH) AF: 0.117 AC: 248 AN: 2116

Alfa AF: 0.103 Hom.: 2991

Bravo AF: 0.102

Asia WGS AF: 0.105 AC: 364 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.110

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	MHC class II deficiency (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.79
DANN	Benign	0.85
PhyloP100		-1.7
PromoterAI		0.44	Neutral
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: rs2229322; hg19: chr16-11016045; COSMIC: COSV60854131; COSMIC: COSV60854131;