chr6-32822322-G-GA

Variant names:

• chr6-32822322-G-GA
• rs61021012
• ENST00000452392.2:c.1933-5371_1933-5370insT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000452392.2(ENSG00000250264):​c.1933-5371_1933-5370insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0834 in 1,113,954 control chromosomes in the GnomAD database, including 340 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.043 (139 hom., cov: 31)
  • Exomes 𝑓: 0.089 (201 hom.)
• Consequence: ENSG00000250264 ENST00000452392.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.143
• Publications: 1 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 6-32822322-G-GA is Benign according to our data. Variant chr6-32822322-G-GA is described in ClinVar as Benign. ClinVar VariationId is 403508.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAP2	NM_018833.3	c.1933-5dupT		splice_region_variant, intron_variant	Intron 11 of 11		NP_061313.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000250264	ENST00000452392.2	c.1933-5371_1933-5370insT		intron_variant	Intron 11 of 14	2		ENSP00000391806.2
TAP2	ENST00000652259.1	c.1933-5_1933-4insT		splice_region_variant, intron_variant	Intron 11 of 11			ENSP00000498827.1
ENSG00000307274	ENST00000824890.1	n.79+1442_79+1443insA		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0431 AC: 6187 AN: 143676 Hom.: 139 Cov.: 31

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0361

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.0373

Gnomad SAS AF: 0.0115

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.0163

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0294

GnomAD2 exomes AF: 0.131 AC: 10306 AN: 78718 AF XY: 0.129

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.0921

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.0894 AC: 86690 AN: 970208 Hom.: 201 Cov.: 27 AF XY: 0.0892 AC XY: 42464 AN XY: 475832

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.125 AC: 2493 AN: 19870

American (AMR) AF: 0.106 AC: 2348 AN: 22154

Ashkenazi Jewish (ASJ) AF: 0.0940 AC: 1494 AN: 15890

East Asian (EAS) AF: 0.113 AC: 2895 AN: 25660

South Asian (SAS) AF: 0.0633 AC: 3193 AN: 50426

European-Finnish (FIN) AF: 0.106 AC: 3437 AN: 32292

Middle Eastern (MID) AF: 0.0536 AC: 213 AN: 3976

European-Non Finnish (NFE) AF: 0.0881 AC: 67074 AN: 761508

Other (OTH) AF: 0.0922 AC: 3543 AN: 38432

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0431 AC: 6191 AN: 143746 Hom.: 139 Cov.: 31 AF XY: 0.0440 AC XY: 3067 AN XY: 69694

African (AFR) AF: 0.0612 AC: 2400 AN: 39242

American (AMR) AF: 0.0361 AC: 522 AN: 14462

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 112 AN: 3356

East Asian (EAS) AF: 0.0374 AC: 187 AN: 5004

South Asian (SAS) AF: 0.0115 AC: 53 AN: 4590

European-Finnish (FIN) AF: 0.0564 AC: 487 AN: 8634

Middle Eastern (MID) AF: 0.0176 AC: 5 AN: 284

European-Non Finnish (NFE) AF: 0.0361 AC: 2360 AN: 65302

Other (OTH) AF: 0.0327 AC: 65 AN: 1990

Alfa AF: 0.0692 Hom.: 5

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61021012; hg19: chr6-32790099; COSMIC: COSV66498381; COSMIC: COSV66498381;