rs138708621

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

Scores

6
11
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.22
Variant links:
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]

Genome browser will be placed here

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
TAP2NM_001290043.2 linkuse as main transcriptc.701T>A p.Leu234Gln missense_variant 4/12 ENST00000374897.4
TAP2NM_018833.3 linkuse as main transcriptc.701T>A p.Leu234Gln missense_variant 4/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TAP2ENST00000374897.4 linkuse as main transcriptc.701T>A p.Leu234Gln missense_variant 4/121 NM_001290043.2 A2Q03519-1

Frequencies

GnomAD3 genomes
AF:
0.000309
AC:
47
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000573
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000219
AC:
54
AN:
246632
Hom.:
0
AF XY:
0.000268
AC XY:
36
AN XY:
134428
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000434
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000643
AC:
939
AN:
1460788
Hom.:
2
Cov.:
33
AF XY:
0.000627
AC XY:
456
AN XY:
726710
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000191
Gnomad4 NFE exome
AF:
0.000792
Gnomad4 OTH exome
AF:
0.000745
GnomAD4 genome
AF:
0.000309
AC:
47
AN:
152320
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000573
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000514
Hom.:
0
Bravo
AF:
0.000272
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000923
AC:
5
ExAC
AF:
0.000203
AC:
24
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000872
EpiControl
AF:
0.000296

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 31, 2022This 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 submitterclinical testingRevvity Omics, RevvityFeb 13, 2020- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 17, 2020Reported 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
.;.;.;T
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.93
D;.;.;.
M_CAP
Pathogenic
0.35
D
MetaRNN
Benign
0.41
T;T;T;T
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
3.4
.;M;.;M
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.9
D;D;.;D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0010
D;D;.;D
Sift4G
Uncertain
0.0080
.;D;D;D
Polyphen
1.0
.;.;.;D
Vest4
0.77, 0.75, 0.76
MVP
0.84
MPC
1.3
ClinPred
0.41
T
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.64
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138708621; hg19: chr6-32803458; API