rs111303994

Variant names:

• chr6-32832650-C-T
• rs111303994
• NM_001290043.2:c.1120G>A

Variant summary

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

The NM_001290043.2(TAP2):​c.1120G>A​(p.Ala374Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00411 in 1,613,046 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (53 hom.)
• Consequence: TAP2 NM_001290043.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.27
• Publications: 8 publications found

Genes affected

TAP2 (HGNC:44): (transporter 2, ATP binding cassette subfamily B member) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. This gene is located 7 kb telomeric to gene family member ABCB2. The protein encoded by this gene is involved in antigen presentation. This protein forms a heterodimer with ABCB2 in order to transport peptides from the cytoplasm to the endoplasmic reticulum. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Alternative splicing of this gene produces products which differ in peptide selectivity and level of restoration of surface expression of MHC class I molecules. [provided by RefSeq, Feb 2014]

TAP2 Gene-Disease associations (from GenCC):

• MHC class I deficiency

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

ENSG00000250264 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050628483).
• BP6: Variant 6-32832650-C-T is Benign according to our data. Variant chr6-32832650-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466362.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 = 0.0138 (2108/152260) while in subpopulation AFR AF = 0.0407 (1689/41534). AF 95% confidence interval is 0.0391. There are 50 homozygotes in GnomAd4. There are 1034 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290043.2. 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
	TAP2	NM_001290043.2	MANE Select	c.1120G>A	p.Ala374Thr	missense	Exon 6 of 12	NP_001276972.1
	TAP2	NM_018833.3		c.1120G>A	p.Ala374Thr	missense	Exon 6 of 12	NP_061313.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP2	ENST00000374897.4	TSL:1 MANE Select	c.1120G>A	p.Ala374Thr	missense	Exon 6 of 12	ENSP00000364032.3
	ENSG00000250264	ENST00000452392.2	TSL:2	c.1120G>A	p.Ala374Thr	missense	Exon 6 of 15	ENSP00000391806.2
	TAP2	ENST00000698449.1		c.1120G>A	p.Ala374Thr	missense	Exon 6 of 13	ENSP00000513734.1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2101 AN: 152142 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00575 AC: 1419 AN: 246652 AF XY: 0.00436

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00938

GnomAD4 exome AF: 0.00310 AC: 4523 AN: 1460786 Hom.: 53 Cov.: 35 AF XY: 0.00285 AC XY: 2071 AN XY: 726710

African (AFR) AF: 0.0388 AC: 1299 AN: 33480

American (AMR) AF: 0.0146 AC: 651 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86258

European-Finnish (FIN) AF: 0.000153 AC: 8 AN: 52324

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.00186 AC: 2064 AN: 1112010

Other (OTH) AF: 0.00700 AC: 423 AN: 60386

GnomAD4 genome AF: 0.0138 AC: 2108 AN: 152260 Hom.: 50 Cov.: 32 AF XY: 0.0139 AC XY: 1034 AN XY: 74448

African (AFR) AF: 0.0407 AC: 1689 AN: 41534

American (AMR) AF: 0.0150 AC: 230 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00213 AC: 145 AN: 68026

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.00581 Hom.: 19

Bravo AF: 0.0166

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0377 AC: 114

ESP6500EA AF: 0.00166 AC: 9

ExAC AF: 0.00614 AC: 725

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	MHC class I deficiency (2)
-	-	1	TAP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0051	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.3
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.52
Sift	Benign	0.062	T
Sift4G	Benign	0.18	T
Polyphen		0.95	P
Vest4		0.20
MVP		0.64
MPC		0.68
ClinPred		0.014	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.39
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: rs111303994; hg19: chr6-32800427; COSMIC: COSV99059133; COSMIC: COSV99059133;