rs61736918

Positions:

• chr6-32838230-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.4C>T​(p.Arg2Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000968 in 1,563,374 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 27)
  • Exomes 𝑓: 0.00063 (3 hom.)
• Consequence: TAP2 NM_001290043.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.180

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=0.008757621).
• BP6: Variant 6-32838230-G-A is Benign according to our data. Variant chr6-32838230-G-A is described in ClinVar as [Benign]. Clinvar id is 466373.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0042 (623/148446) while in subpopulation AFR AF= 0.0124 (496/40046). AF 95% confidence interval is 0.0115. There are 5 homozygotes in gnomad4. There are 316 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP2	NM_001290043.2	c.4C>T	p.Arg2Trp	missense_variant	2/12	ENST00000374897.4
TAP2	NM_018833.3	c.4C>T	p.Arg2Trp	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP2	ENST00000374897.4	c.4C>T	p.Arg2Trp	missense_variant	2/12	1	NM_001290043.2	A2

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 624 AN: 148328 Hom.: 5 Cov.: 27

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00638

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000328

Gnomad OTH AF: 0.00503

GnomAD3 exomes AF: 0.00194 AC: 400 AN: 206168 Hom.: 1 AF XY: 0.00157 AC XY: 176 AN XY: 111850

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.00580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000382

Gnomad OTH exome AF: 0.000809

GnomAD4 exome AF: 0.000630 AC: 891 AN: 1414928 Hom.: 3 Cov.: 35 AF XY: 0.000543 AC XY: 380 AN XY: 700420

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.00586

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00420 AC: 623 AN: 148446 Hom.: 5 Cov.: 27 AF XY: 0.00437 AC XY: 316 AN XY: 72264

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.00637

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000328

Gnomad4 OTH AF: 0.00497

Alfa AF: 0.000898 Hom.: 2

Bravo AF: 0.00567

ESP6500AA AF: 0.0126 AC: 38

ESP6500EA AF: 0.000738 AC: 4

ExAC AF: 0.00164 AC: 194

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.089	.;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.86	D;.;.;.
MetaRNN	Benign	0.0088	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.6	.;L;.;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N;N;.;N
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.035	.;D;D;D
Polyphen		0.0020	.;.;.;B
Vest4		0.12, 0.11, 0.12
MVP		0.39
MPC		0.47
ClinPred		0.035	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs61736918; hg19: chr6-32806007; COSMIC: COSV66487501; COSMIC: COSV66487501;