chr6-32832787-G-C

Position:

• chr6-32832787-G-C

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.983C>G​(p.Ala328Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000539 in 1,612,810 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A328A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00063 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (9 hom.)
• Consequence: TAP2 NM_001290043.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 3.52

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=0.010731518).
• BP6: Variant 6-32832787-G-C is Benign according to our data. Variant chr6-32832787-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 534733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32832787-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000631 (96/152212) while in subpopulation SAS AF= 0.0102 (49/4824). AF 95% confidence interval is 0.00789. There are 3 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP2	NM_001290043.2	c.983C>G	p.Ala328Gly	missense_variant	6/12	ENST00000374897.4
TAP2	NM_018833.3	c.983C>G	p.Ala328Gly	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP2	ENST00000374897.4	c.983C>G	p.Ala328Gly	missense_variant	6/12	1	NM_001290043.2	A2

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152094 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00104 AC: 257 AN: 246388 Hom.: 3 AF XY: 0.00141 AC XY: 189 AN XY: 134334

Gnomad AFR exome AF: 0.000331

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.00714

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000530 AC: 774 AN: 1460598 Hom.: 9 Cov.: 35 AF XY: 0.000717 AC XY: 521 AN XY: 726634

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000856

Gnomad4 SAS exome AF: 0.00660

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152212 Hom.: 3 Cov.: 32 AF XY: 0.000726 AC XY: 54 AN XY: 74428

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00445

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000385

ExAC AF: 0.00116 AC: 137

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

MHC class I deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;.;.;D
Eigen	Benign	0.17
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;.;.;.
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.6	.;H;.;H
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D;D;.;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.010	D;D;.;D
Sift4G	Benign	0.068	.;T;T;T
Polyphen		0.13	.;.;.;B
Vest4		0.22, 0.23, 0.22
MVP		0.60
MPC		0.76
ClinPred		0.11	T
GERP RS		5.0
Varity_R		0.51
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs148663600; hg19: chr6-32800564;