rs16870908

Variant names:

• chr6-32822312-G-A
• rs16870908
• ENST00000452392.2:c.1933-5360C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/16 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
• Publications: 17 publications found

Genes affected

ENSG00000250264 (HGNC:):

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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• MHC class I deficiency 1

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 403507.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018833.3. 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_018833.3		c.1939C>T	p.Leu647Phe	missense	Exon 12 of 12	NP_061313.2	Q9UP03

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000250264	ENST00000452392.2	TSL:2	c.1933-5360C>T		intron	N/A	ENSP00000391806.2	E7ENX8
	TAP2	ENST00000652259.1		c.1939C>T	p.Leu647Phe	missense	Exon 12 of 12	ENSP00000498827.1	Q03519-2
	ENSG00000307274	ENST00000824890.1		n.79+1432G>A		intron	N/A

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

GnomAD2 exomes AF: 0.0613 AC: 10961 AN: 178952 AF XY: 0.0582

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 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

African (AFR) AF: 0.209 AC: 6378 AN: 30576

American (AMR) AF: 0.0442 AC: 1690 AN: 38264

Ashkenazi Jewish (ASJ) AF: 0.0275 AC: 686 AN: 24990

East Asian (EAS) AF: 0.0459 AC: 1776 AN: 38658

South Asian (SAS) AF: 0.0199 AC: 1566 AN: 78766

European-Finnish (FIN) AF: 0.0944 AC: 4690 AN: 49658

Middle Eastern (MID) AF: 0.0403 AC: 222 AN: 5506

European-Non Finnish (NFE) AF: 0.0451 AC: 47543 AN: 1053842

Other (OTH) AF: 0.0515 AC: 2942 AN: 57180

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

African (AFR) AF: 0.224 AC: 9252 AN: 41264

American (AMR) AF: 0.0637 AC: 970 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 100 AN: 3460

East Asian (EAS) AF: 0.0388 AC: 200 AN: 5154

South Asian (SAS) AF: 0.0283 AC: 135 AN: 4768

European-Finnish (FIN) AF: 0.101 AC: 1044 AN: 10380

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.0547 AC: 3712 AN: 67878

Other (OTH) AF: 0.0910 AC: 191 AN: 2100

Alfa AF: 0.0690 Hom.: 1679

Bravo AF: 0.106

Asia WGS AF: 0.0490 AC: 172 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	TAP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
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
PhyloP100		-0.32
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.16
Sift	Benign	0.21	T
Sift4G	Benign	0.084	T
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs16870908;

hg19: chr6-32790089;

COSMIC: COSV107494534;

COSMIC: COSV107494534;