rs74770812

Positions:

• chr6-32829506-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001290043.2(TAP2):​c.1826C>T​(p.Ala609Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,614,102 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A609A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0095 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (20 hom.)
• Consequence: TAP2 NM_001290043.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.65

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014017075).
• BP6: Variant 6-32829506-G-A is Benign according to our data. Variant chr6-32829506-G-A is described in ClinVar as [Benign]. Clinvar id is 466369.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00951 (1449/152286) while in subpopulation AFR AF= 0.0317 (1319/41558). AF 95% confidence interval is 0.0303. There are 13 homozygotes in gnomad4. There are 654 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP2	NM_001290043.2	c.1826C>T	p.Ala609Val	missense_variant	11/12	ENST00000374897.4
TAP2	NM_018833.3	c.1826C>T	p.Ala609Val	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP2	ENST00000374897.4	c.1826C>T	p.Ala609Val	missense_variant	11/12	1	NM_001290043.2	A2

Frequencies

GnomAD3 genomes AF: 0.00951 AC: 1447 AN: 152168 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00276 AC: 694 AN: 251316 Hom.: 8 AF XY: 0.00213 AC XY: 289 AN XY: 135824

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00124 AC: 1818 AN: 1461816 Hom.: 20 Cov.: 54 AF XY: 0.00113 AC XY: 821 AN XY: 727204

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000418

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00951 AC: 1449 AN: 152286 Hom.: 13 Cov.: 32 AF XY: 0.00878 AC XY: 654 AN XY: 74466

Gnomad4 AFR AF: 0.0317

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00225 Hom.: 6

Bravo AF: 0.0111

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0327 AC: 144

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00330 AC: 400

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class I deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.023
DANN	Uncertain	0.99
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.81	T;.;.;.
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-0.79	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.7	N;N;.;N
REVEL	Benign	0.24
Sift	Benign	0.23	T;T;.;T
Polyphen		0.091	.;.;.;B
Vest4		0.077, 0.065, 0.067
MVP		0.22
MPC		0.50
ClinPred		0.016	T
GERP RS		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.41

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: rs74770812; hg19: chr6-32797283; COSMIC: COSV100886980; COSMIC: COSV100886980;