6-32830705-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001290043.2(TAP2):c.1374G>A(p.Thr458=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,613,042 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T458T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (36 hom.)
• Consequence: TAP2 NM_001290043.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.27

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-32830705-C-T is Benign according to our data. Variant chr6-32830705-C-T is described in ClinVar as [Benign]. Clinvar id is 466366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1627/152300) while in subpopulation AFR AF= 0.0298 (1240/41550). AF 95% confidence interval is 0.0285. There are 28 homozygotes in gnomad4. There are 807 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP2	NM_001290043.2	c.1374G>A	p.Thr458=	synonymous_variant	8/12	ENST00000374897.4
TAP2	NM_018833.3	c.1374G>A	p.Thr458=	synonymous_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP2	ENST00000374897.4	c.1374G>A	p.Thr458=	synonymous_variant	8/12	1	NM_001290043.2	A2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1620 AN: 152182 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00476 AC: 1174 AN: 246544 Hom.: 9 AF XY: 0.00367 AC XY: 493 AN XY: 134394

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000231

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00889

GnomAD4 exome AF: 0.00270 AC: 3945 AN: 1460742 Hom.: 36 Cov.: 36 AF XY: 0.00252 AC XY: 1831 AN XY: 726694

Gnomad4 AFR exome AF: 0.0274

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.000153

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.00603

GnomAD4 genome AF: 0.0107 AC: 1627 AN: 152300 Hom.: 28 Cov.: 32 AF XY: 0.0108 AC XY: 807 AN XY: 74470

Gnomad4 AFR AF: 0.0298

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00287 Hom.: 4

Bravo AF: 0.0130

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class I deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

TAP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 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_noAF	Benign	-0.74
Cadd	Benign	0.29
Dann	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs149495208; hg19: chr6-32798482;