chr6-32835681-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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

Publications

2 publications found

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 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

TAP2 links:

ENSG00000250264 (HGNC:):

ENSG00000250264 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, REVEL, 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. 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

GnomAD2 exomes

AF:

0.000219

AC:

AN:

246632

AF XY:

0.000268

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 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

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000792

AC:

881

AN:

1112006

Other (OTH)

AF:

0.000745

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000309

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41568

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000573

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

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

PhyloP100

4.2

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

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over