6-32838190-A-G

Variant names:

• chr6-32838190-A-G
• rs55827768
• NM_001290043.2:c.44T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000374897.4(TAP2):​c.44T>C​(p.Val15Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,592,592 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (15 hom., cov: 27)
  • Exomes 𝑓: 0.0027 (49 hom.)
• Consequence: TAP2 ENST00000374897.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.127
• Publications: 8 publications found

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]

TAP2 Gene-Disease associations (from GenCC):

• MHC class I deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000250264 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048670173).
• BP6: Variant 6-32838190-A-G is Benign according to our data. Variant chr6-32838190-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00789 (1186/150398) while in subpopulation AFR AF = 0.0222 (904/40784). AF 95% confidence interval is 0.021. There are 15 homozygotes in GnomAd4. There are 590 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374897.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP2	NM_001290043.2	MANE Select	c.44T>C	p.Val15Ala	missense	Exon 2 of 12	NP_001276972.1
	TAP2	NM_018833.3		c.44T>C	p.Val15Ala	missense	Exon 2 of 12	NP_061313.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP2	ENST00000374897.4	TSL:1 MANE Select	c.44T>C	p.Val15Ala	missense	Exon 2 of 12	ENSP00000364032.3
	ENSG00000250264	ENST00000452392.2	TSL:2	c.44T>C	p.Val15Ala	missense	Exon 2 of 15	ENSP00000391806.2
	TAP2	ENST00000698449.1		c.44T>C	p.Val15Ala	missense	Exon 2 of 13	ENSP00000513734.1

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1186 AN: 150280 Hom.: 15 Cov.: 27

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00339

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00880

GnomAD2 exomes AF: 0.00460 AC: 1064 AN: 231482 AF XY: 0.00505

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.000486

Gnomad EAS exome AF: 0.00151

Gnomad FIN exome AF: 0.000146

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00270 AC: 3892 AN: 1442194 Hom.: 49 Cov.: 35 AF XY: 0.00307 AC XY: 2195 AN XY: 715764

African (AFR) AF: 0.0239 AC: 787 AN: 32958

American (AMR) AF: 0.00247 AC: 106 AN: 42962

Ashkenazi Jewish (ASJ) AF: 0.000283 AC: 7 AN: 24702

East Asian (EAS) AF: 0.000861 AC: 34 AN: 39470

South Asian (SAS) AF: 0.0149 AC: 1250 AN: 84032

European-Finnish (FIN) AF: 0.0000775 AC: 4 AN: 51640

Middle Eastern (MID) AF: 0.0176 AC: 88 AN: 5004

European-Non Finnish (NFE) AF: 0.00128 AC: 1412 AN: 1102030

Other (OTH) AF: 0.00343 AC: 204 AN: 59396

GnomAD4 genome AF: 0.00789 AC: 1186 AN: 150398 Hom.: 15 Cov.: 27 AF XY: 0.00804 AC XY: 590 AN XY: 73370

African (AFR) AF: 0.0222 AC: 904 AN: 40784

American (AMR) AF: 0.00338 AC: 51 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3456

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5146

South Asian (SAS) AF: 0.0135 AC: 63 AN: 4664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10412

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00200 AC: 135 AN: 67596

Other (OTH) AF: 0.00870 AC: 18 AN: 2068

Alfa AF: 0.00403 Hom.: 8

Bravo AF: 0.00855

ESP6500AA AF: 0.0235 AC: 71

ESP6500EA AF: 0.00185 AC: 10

ExAC AF: 0.00496 AC: 587

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MHC class I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	10
DANN	Benign	0.52
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.13
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.55	N
REVEL	Uncertain	0.38
Sift	Benign	0.16	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.058
MVP		0.12
MPC		0.54
ClinPred		0.0016	T
GERP RS		-7.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.35
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55827768; hg19: chr6-32805967; COSMIC: COSV66488486; COSMIC: COSV66488486;