rs138708621
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP4BS2
The NM_001290043.2(TAP2):c.701T>A(p.Leu234Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000611 in 1,613,108 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00064 ( 2 hom. )
Consequence
TAP2
NM_001290043.2 missense
NM_001290043.2 missense
Scores
6
11
1
Clinical Significance
Conservation
PhyloP100: 4.22
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.4076917).
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TAP2 | NM_001290043.2 | c.701T>A | p.Leu234Gln | missense_variant | 4/12 | ENST00000374897.4 | |
TAP2 | NM_018833.3 | c.701T>A | p.Leu234Gln | missense_variant | 4/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TAP2 | ENST00000374897.4 | c.701T>A | p.Leu234Gln | missense_variant | 4/12 | 1 | NM_001290043.2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000309 AC: 47AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000219 AC: 54AN: 246632Hom.: 0 AF XY: 0.000268 AC XY: 36AN XY: 134428
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GnomAD4 exome AF: 0.000643 AC: 939AN: 1460788Hom.: 2 Cov.: 33 AF XY: 0.000627 AC XY: 456AN XY: 726710
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GnomAD4 genome AF: 0.000309 AC: 47AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74486
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
MHC class I deficiency Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 31, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 234 of the TAP2 protein (p.Leu234Gln). This variant is present in population databases (rs138708621, gnomAD 0.04%). This missense change has been observed in individual(s) with common variable immunodeficiency (CVID) (PMID: 26122175). ClinVar contains an entry for this variant (Variation ID: 574783). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 13, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2020 | Reported in the heterozygous state in a proband with combined variable immune deficiency, but limited clinical information was provided, and another variant was not identified on the other TAP2 allele (van Schouwenburg et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26122175) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;.;.
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;M;.;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;D
Sift4G
Uncertain
.;D;D;D
Polyphen
1.0
.;.;.;D
Vest4
0.77, 0.75, 0.76
MVP
MPC
1.3
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at