rs1800454

chr6-32832635-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001290043.2(TAP2):c.1135G>A(p.Val379Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,612,908 control chromosomes in the GnomAD database, including 16,466 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V379L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1653 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14813 hom.)
• Consequence: TAP2 NM_001290043.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -2.53

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002161771).
• BP6: Variant 6-32832635-C-T is Benign according to our data. Variant chr6-32832635-C-T is described in ClinVar as [Benign]. Clinvar id is 13724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32832635-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP2	NM_001290043.2	c.1135G>A	p.Val379Ile	missense_variant	6/12	ENST00000374897.4
TAP2	NM_018833.3	c.1135G>A	p.Val379Ile	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP2	ENST00000374897.4	c.1135G>A	p.Val379Ile	missense_variant	6/12	1	NM_001290043.2	A2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21865 AN: 152028 Hom.: 1650 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.0895

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.136

GnomAD3 exomes AF: 0.144 AC: 35501 AN: 246610 Hom.: 2695 AF XY: 0.140 AC XY: 18796 AN XY: 134420

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.0873

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.140 AC: 204942 AN: 1460762 Hom.: 14813 Cov.: 37 AF XY: 0.139 AC XY: 100866 AN XY: 726696

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.0904

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome AF: 0.144 AC: 21888 AN: 152146 Hom.: 1653 Cov.: 32 AF XY: 0.144 AC XY: 10704 AN XY: 74370

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.0889

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.136

Alfa AF: 0.142 Hom.: 3404

Bravo AF: 0.146

TwinsUK AF: 0.146 AC: 543

ALSPAC AF: 0.145 AC: 557

ESP6500AA AF: 0.149 AC: 450

ESP6500EA AF: 0.137 AC: 742

ExAC AF: 0.142 AC: 16766

Asia WGS AF: 0.164 AC: 572 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.152

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class I deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

PEPTIDE TRANSPORTER PSF2 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

May 01, 1992

- -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	0.0020
Dann	Benign	0.74
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.44	T;.;.;.
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.23	N;N;.;N
REVEL	Benign	0.20
Sift	Benign	0.49	T;T;.;T
Polyphen		0.029	.;.;.;B
Vest4		0.070, 0.071
MPC		0.37
ClinPred		0.0078	T
GERP RS		-9.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800454; hg19: chr6-32800412; COSMIC: COSV66499344; COSMIC: COSV66499344;