6-32828974-T-C

Position:

• chr6-32828974-T-C

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.1993A>G​(p.Thr665Ala) variant causes a missense change. The variant allele was found at a frequency of 0.269 in 1,549,446 control chromosomes in the GnomAD database, including 58,603 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5642 hom., cov: 30)
  • Exomes 𝑓: 0.27 (52961 hom.)
• Consequence: TAP2 NM_001290043.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.70

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=0.031624883).
• BP6: Variant 6-32828974-T-C is Benign according to our data. Variant chr6-32828974-T-C is described in ClinVar as [Benign]. Clinvar id is 403511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32828974-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP2	NM_001290043.2	c.1993A>G	p.Thr665Ala	missense_variant	12/12	ENST00000374897.4
TAP2	NM_018833.3	c.1932+426A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP2	ENST00000374897.4	c.1993A>G	p.Thr665Ala	missense_variant	12/12	1	NM_001290043.2	A2

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40167 AN: 151784 Hom.: 5632 Cov.: 30

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.291

GnomAD3 exomes AF: 0.313 AC: 47971 AN: 153132 Hom.: 7901 AF XY: 0.315 AC XY: 25954 AN XY: 82418

Gnomad AFR exome AF: 0.176

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.345

Gnomad EAS exome AF: 0.359

Gnomad SAS exome AF: 0.394

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.298

GnomAD4 exome AF: 0.269 AC: 376632 AN: 1397544 Hom.: 52961 Cov.: 43 AF XY: 0.273 AC XY: 188203 AN XY: 689444

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.347

Gnomad4 ASJ exome AF: 0.350

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.335

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.280

GnomAD4 genome AF: 0.265 AC: 40199 AN: 151902 Hom.: 5642 Cov.: 30 AF XY: 0.273 AC XY: 20265 AN XY: 74242

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.344

Gnomad4 EAS AF: 0.366

Gnomad4 SAS AF: 0.399

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.292

Alfa AF: 0.271 Hom.: 12023

Bravo AF: 0.259

TwinsUK AF: 0.230 AC: 851

ALSPAC AF: 0.239 AC: 921

ESP6500AA AF: 0.156 AC: 397

ESP6500EA AF: 0.214 AC: 1026

ExAC AF: 0.190 AC: 17273

Asia WGS AF: 0.365 AC: 1269 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class I deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.38	.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.032	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.4	.;D
REVEL	Benign	0.29
Sift	Benign	0.037	.;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.19	.;B
Vest4		0.082
ClinPred		0.042	T
GERP RS		3.4
Varity_R		0.067
gMVP		0.48

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: rs241447; hg19: chr6-32796751; COSMIC: COSV66497946; COSMIC: COSV66497946;