rs1800454

Variant names:

• chr6-32832635-C-A
• rs1800454
• NM_001290043.2:c.1135G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32832635-C-A
• chr6-32832635-C-G
• chr6-32832635-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001290043.2(TAP2):​c.1135G>T​(p.Val379Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V379I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TAP2 NM_001290043.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.53
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08899394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAP2	NM_001290043.2	c.1135G>T	p.Val379Leu	missense_variant	Exon 6 of 12	ENST00000374897.4	NP_001276972.1
TAP2	NM_018833.3	c.1135G>T	p.Val379Leu	missense_variant	Exon 6 of 12		NP_061313.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAP2	ENST00000374897.4	c.1135G>T	p.Val379Leu	missense_variant	Exon 6 of 12	1	NM_001290043.2	ENSP00000364032.3
ENSG00000250264	ENST00000452392.2	c.1135G>T	p.Val379Leu	missense_variant	Exon 6 of 15	2		ENSP00000391806.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class I deficiency Uncertain:1

Jun 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 379 of the TAP2 protein (p.Val379Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TAP2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.0010
DANN	Benign	0.71
DEOGEN2	Benign	0.15	.;.;.;T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.60	T;.;.;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.089	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.66	.;N;.;N
PhyloP100		-2.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.12	N;N;.;N
REVEL	Uncertain	0.35
Sift	Benign	0.38	T;T;.;T
Sift4G	Benign	0.96	.;T;T;T
Polyphen		0.0030	.;.;.;B
Vest4		0.081, 0.079, 0.077
MutPred		0.72		Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);
MVP		0.19
MPC		0.45
ClinPred		0.062	T
GERP RS		-9.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.23
Mutation Taster		=99/1	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: rs1800454; hg19: chr6-32800412;