6-32822312-G-A

Position:

• chr6-32822312-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018833.3(TAP2):​c.1939C>T​(p.Leu647Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0544 in 1,528,880 control chromosomes in the GnomAD database, including 3,629 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (1226 hom., cov: 31)
  • Exomes 𝑓: 0.049 (2403 hom.)
• Consequence: TAP2 NM_018833.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.319

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009473324).
• BP6: Variant 6-32822312-G-A is Benign according to our data. Variant chr6-32822312-G-A is described in ClinVar as [Benign]. Clinvar id is 403507.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32822312-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAP2	NM_018833.3	c.1939C>T	p.Leu647Phe	missense_variant	12/12		NP_061313.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAP2	ENST00000652259.1	c.1939C>T	p.Leu647Phe	missense_variant	12/12			ENSP00000498827

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15664 AN: 151328 Hom.: 1224 Cov.: 31

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0638

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.0387

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0897

Gnomad NFE AF: 0.0547

Gnomad OTH AF: 0.0885

GnomAD3 exomes AF: 0.0613 AC: 10961 AN: 178952 Hom.: 531 AF XY: 0.0582 AC XY: 5599 AN XY: 96272

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.0425

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.0343

Gnomad SAS exome AF: 0.0209

Gnomad FIN exome AF: 0.0952

Gnomad NFE exome AF: 0.0568

Gnomad OTH exome AF: 0.0565

GnomAD4 exome AF: 0.0490 AC: 67493 AN: 1377440 Hom.: 2403 Cov.: 27 AF XY: 0.0480 AC XY: 32809 AN XY: 683374

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.0442

Gnomad4 ASJ exome AF: 0.0275

Gnomad4 EAS exome AF: 0.0459

Gnomad4 SAS exome AF: 0.0199

Gnomad4 FIN exome AF: 0.0944

Gnomad4 NFE exome AF: 0.0451

Gnomad4 OTH exome AF: 0.0515

GnomAD4 genome AF: 0.104 AC: 15689 AN: 151440 Hom.: 1226 Cov.: 31 AF XY: 0.104 AC XY: 7671 AN XY: 73984

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.0637

Gnomad4 ASJ AF: 0.0289

Gnomad4 EAS AF: 0.0388

Gnomad4 SAS AF: 0.0283

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.0547

Gnomad4 OTH AF: 0.0910

Alfa AF: 0.0631 Hom.: 642

Bravo AF: 0.106

TwinsUK AF: 0.0523 AC: 194

ALSPAC AF: 0.0516 AC: 199

ESP6500AA AF: 0.202 AC: 599

ESP6500EA AF: 0.0475 AC: 256

ExAC AF: 0.0535 AC: 6086

Asia WGS AF: 0.0490 AC: 172 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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 -

TAP2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.6
DANN	Benign	0.52
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.000050	N
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.16
Sift	Benign	0.21	T
Sift4G	Benign	0.084	T
Vest4		0.017
MPC		0.49
ClinPred		0.00094	T
GERP RS		0.85

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: rs16870908; hg19: chr6-32790089;