chr6-32832635-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/20 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
• Publications: 67 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: Benign. The variant received -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 VariationId is 13724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290043.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP2	NM_001290043.2	MANE Select	c.1135G>A	p.Val379Ile	missense	Exon 6 of 12	NP_001276972.1
	TAP2	NM_018833.3		c.1135G>A	p.Val379Ile	missense	Exon 6 of 12	NP_061313.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP2	ENST00000374897.4	TSL:1 MANE Select	c.1135G>A	p.Val379Ile	missense	Exon 6 of 12	ENSP00000364032.3
	ENSG00000250264	ENST00000452392.2	TSL:2	c.1135G>A	p.Val379Ile	missense	Exon 6 of 15	ENSP00000391806.2
	TAP2	ENST00000698449.1		c.1135G>A	p.Val379Ile	missense	Exon 6 of 13	ENSP00000513734.1

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

GnomAD2 exomes AF: 0.144 AC: 35501 AN: 246610 AF XY: 0.140

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 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

African (AFR) AF: 0.148 AC: 4963 AN: 33478

American (AMR) AF: 0.163 AC: 7284 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3150 AN: 26136

East Asian (EAS) AF: 0.168 AC: 6681 AN: 39698

South Asian (SAS) AF: 0.0904 AC: 7794 AN: 86258

European-Finnish (FIN) AF: 0.139 AC: 7297 AN: 52316

Middle Eastern (MID) AF: 0.153 AC: 884 AN: 5768

European-Non Finnish (NFE) AF: 0.142 AC: 158158 AN: 1111998

Other (OTH) AF: 0.145 AC: 8731 AN: 60386

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

African (AFR) AF: 0.153 AC: 6335 AN: 41500

American (AMR) AF: 0.139 AC: 2120 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 404 AN: 3472

East Asian (EAS) AF: 0.186 AC: 966 AN: 5182

South Asian (SAS) AF: 0.0889 AC: 428 AN: 4814

European-Finnish (FIN) AF: 0.146 AC: 1541 AN: 10586

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9622 AN: 67996

Other (OTH) AF: 0.136 AC: 286 AN: 2110

Alfa AF: 0.141 Hom.: 7115

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	MHC class I deficiency (2)
-	-	1	not specified (1)
-	-	1	TAP2 POLYMORPHISM (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.14	T
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
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-2.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.20
Sift	Benign	0.49	T
Sift4G	Benign	0.85	T
Polyphen		0.029	B
Vest4		0.070
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
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV66499344; COSMIC: COSV66499344;