rs138708621

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4BS1_SupportingBS2

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

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]

TAP2 links:

ENSG00000250264 (HGNC:):

ENSG00000250264 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000309 (47/152320) while in subpopulation NFE AF= 0.000573 (39/68032). AF 95% confidence interval is 0.000431. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAP2	NM_001290043.2 link	c.701T>A	p.Leu234Gln	missense_variant	Exon 4 of 12	ENST00000374897.4	NP_001276972.1	Q03519-1Q5JNW1
TAP2	NM_018833.3 link	c.701T>A	p.Leu234Gln	missense_variant	Exon 4 of 12		NP_061313.2	Q03519-2Q9UP03

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAP2	ENST00000374897.4 link	c.701T>A	p.Leu234Gln	missense_variant	Exon 4 of 12	1	NM_001290043.2	ENSP00000364032.3		Q03519-1
ENSG00000250264	ENST00000452392.2 link	c.701T>A	p.Leu234Gln	missense_variant	Exon 4 of 15	2		ENSP00000391806.2		E7ENX8

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152202

Hom.:

Cov.:

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:

AN:

246632

Hom.:

AF XY:

0.000268

AC XY:

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.:

Cov.:

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:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

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.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000923

AC:

ExAC

AF:

0.000203

AC:

Asia WGS

AF:

0.000289

AC:

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

Feb 13, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Uncertain:1

Feb 18, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (PMID: 26122175); 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

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;.;.;T

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;.;.;.

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.4

.;M;.;M

PrimateAI

Uncertain

0.64

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over