rs4148876

Positions:

• chr6-32829016-G-A

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.1951C>T​(p.Arg651Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.069 in 1,549,556 control chromosomes in the GnomAD database, including 4,055 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R651L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.058 (318 hom., cov: 31)
  • Exomes 𝑓: 0.070 (3737 hom.)
• Consequence: TAP2 NM_001290043.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.818

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=0.0017689466).
• BP6: Variant 6-32829016-G-A is Benign according to our data. Variant chr6-32829016-G-A is described in ClinVar as [Benign]. Clinvar id is 1164495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP2	NM_001290043.2	c.1951C>T	p.Arg651Cys	missense_variant	12/12	ENST00000374897.4
TAP2	NM_018833.3	c.1932+384C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP2	ENST00000374897.4	c.1951C>T	p.Arg651Cys	missense_variant	12/12	1	NM_001290043.2	A2

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8824 AN: 152136 Hom.: 316 Cov.: 31

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0817

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0738

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.0740

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0722

Gnomad OTH AF: 0.0516

GnomAD3 exomes AF: 0.0764 AC: 11720 AN: 153326 Hom.: 560 AF XY: 0.0733 AC XY: 6043 AN XY: 82410

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.0768

Gnomad SAS exome AF: 0.0562

Gnomad FIN exome AF: 0.0730

Gnomad NFE exome AF: 0.0702

Gnomad OTH exome AF: 0.0694

GnomAD4 exome AF: 0.0702 AC: 98067 AN: 1397302 Hom.: 3737 Cov.: 36 AF XY: 0.0695 AC XY: 47910 AN XY: 689074

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.0554

Gnomad4 FIN exome AF: 0.0736

Gnomad4 NFE exome AF: 0.0691

Gnomad4 OTH exome AF: 0.0670

GnomAD4 genome AF: 0.0580 AC: 8829 AN: 152254 Hom.: 318 Cov.: 31 AF XY: 0.0581 AC XY: 4326 AN XY: 74452

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0820

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.0740

Gnomad4 SAS AF: 0.0527

Gnomad4 FIN AF: 0.0740

Gnomad4 NFE AF: 0.0722

Gnomad4 OTH AF: 0.0506

Alfa AF: 0.0721 Hom.: 797

Bravo AF: 0.0580

TwinsUK AF: 0.0739 AC: 274

ALSPAC AF: 0.0688 AC: 265

ESP6500AA AF: 0.0118 AC: 30

ESP6500EA AF: 0.0542 AC: 259

ExAC AF: 0.0351 AC: 3393

Asia WGS AF: 0.0580 AC: 202 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class I deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.055	N
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.7	.;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.21	.;N
REVEL	Uncertain	0.29
Sift	Benign	0.19	.;T
Sift4G	Benign	0.20	T;T
Polyphen		1.0	.;D
Vest4		0.076
ClinPred		0.0067	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs4148876; hg19: chr6-32796793; COSMIC: COSV66498462; COSMIC: COSV66498462;